Pandemic (H1N1) 2009 – update 63

Weekly update

In the southern hemisphere, most countries (represented by Chile, Argentina, New Zealand, and Australia) appear to have passed their peak of influenza activity and have either returned to baseline levels or are experiencing focal activity in later affected areas; while a few others (represented by South Africa and Bolivia) continue to experience high levels of influenza activity.
Many countries in tropical regions (represented by Central America and tropical regions of Asia), continue to see increasing or sustained high levels of influenza activity with some countries reporting moderate strains on the healthcare system. In temperate areas of the northern hemisphere (represented by North America, Europe, and Central Asia), influenza and respiratory disease activity remains low overall, with some countries experiencing localized outbreaks. In Japan, the level of influenza activity has passed the seasonal epidemic threshold, signaling a very early beginning to the annual influenza season.
Pandemic H1N1 influenza virus continues to be the predominant circulating strain of influenza, both in the northern and southern hemisphere. Antiviral susceptibility testing has increased in several countries, confirming that pandemic H1N1 influenza virus remains sensitive to the antiviral oseltamivir, except for sporadic reports of oseltamivir resistant pandemic H1N1 virus detailed in the previous web update (No. 62).

http://www.who.int/csr/don/2009_08_28/en/index.html

Pandemic (H1N1) 2009 briefing note 9

Preparing for the second wave: lessons from current outbreaks

28 AUGUST 2009 | GENEVA –

Monitoring of outbreaks from different parts of the world provides sufficient information to make some tentative conclusions about how the influenza pandemic might evolve in the coming months.

WHO is advising countries in the northern hemisphere to prepare for a second wave of pandemic spread. Countries with tropical climates, where the pandemic virus arrived later than elsewhere, also need to prepare for an increasing number of cases.

Countries in temperate parts of the southern hemisphere should remain vigilant. As experience has shown, localized “hot spots” of increasing transmission can continue to occur even when the pandemic has peaked at the national level.

H1N1 now the dominant virus strain

Evidence from multiple outbreak sites demonstrates that the H1N1 pandemic virus has rapidly established itself and is now the dominant influenza strain in most parts of the world. The pandemic will persist in the coming months as the virus continues to move through susceptible populations.

Close monitoring of viruses by a WHO network of laboratories shows that viruses from all outbreaks remain virtually identical. Studies have detected no signs that the virus has mutated to a more virulent or lethal form.

Likewise, the clinical picture of pandemic influenza is largely consistent across all countries. The overwhelming majority of patients continue to experience mild illness. Although the virus can cause very severe and fatal illness, also in young and healthy people, the number of such cases remains small.

Large populations susceptible to infection

While these trends are encouraging, large numbers of people in all countries remain susceptible to infection. Even if the current pattern of usually mild illness continues, the impact of the pandemic during the second wave could worsen as larger numbers of people become infected.

Larger numbers of severely ill patients requiring intensive care are likely to be the most urgent burden on health services, creating pressures that could overwhelm intensive care units and possibly disrupt the provision of care for other diseases.

Monitoring for drug resistance

At present, only a handful of pandemic viruses resistant to oseltamivir have been detected worldwide, despite the administration of many millions of treatment courses of antiviral drugs. All of these cases have been extensively investigated, and no instances of onward transmission of drug-resistant virus have been documented to date. Intense monitoring continues, also through the WHO network of laboratories.

Not the same as seasonal influenza

Current evidence points to some important differences between patterns of illness reported during the pandemic and those seen during seasonal epidemics of influenza.

The age groups affected by the pandemic are generally younger. This is true for those most frequently infected, and especially so for those experiencing severe or fatal illness.

To date, most severe cases and deaths have occurred in adults under the age of 50 years, with deaths in the elderly comparatively rare. This age distribution is in stark contrast with seasonal influenza, where around 90% of severe and fatal cases occur in people 65 years of age or older.

Severe respiratory failure

Perhaps most significantly, clinicians from around the world are reporting a very severe form of disease, also in young and otherwise healthy people, which is rarely seen during seasonal influenza infections. In these patients, the virus directly infects the lung, causing severe respiratory failure. Saving these lives depends on highly specialized and demanding care in intensive care units, usually with long and costly stays.

During the winter season in the southern hemisphere, several countries have viewed the need for intensive care as the greatest burden on health services. Some cities in these countries report that nearly 15 percent of hospitalized cases have required intensive care.

Preparedness measures need to anticipate this increased demand on intensive care units, which could be overwhelmed by a sudden surge in the number of severe cases.

Vulnerable groups

An increased risk during pregnancy is now consistently well-documented across countries. This risk takes on added significance for a virus, like this one, that preferentially infects younger people.

Data continue to show that certain medical conditions increase the risk of severe and fatal illness. These include respiratory disease, notably asthma, cardiovascular disease, diabetes and immunosuppression.

When anticipating the impact of the pandemic as more people become infected, health officials need to be aware that many of these predisposing conditions have become much more widespread in recent decades, thus increasing the pool of vulnerable people.

Obesity, which is frequently present in severe and fatal cases, is now a global epidemic. WHO estimates that, worldwide, more than 230 million people suffer from asthma, and more than 220 million people have diabetes.

Moreover, conditions such as asthma and diabetes are not usually considered killer diseases, especially in children and young adults. Young deaths from such conditions, precipitated by infection with the H1N1 virus, can be another dimension of the pandemic’s impact.

Higher risk of hospitalization and death

Several early studies show a higher risk of hospitalization and death among certain subgroups, including minority groups and indigenous populations. In some studies, the risk in these groups is four to five times higher than in the general population.

Although the reasons are not fully understood, possible explanations include lower standards of living and poor overall health status, including a high prevalence of conditions such as asthma, diabetes and hypertension.

Implications for the developing world

Such findings are likely to have growing relevance as the pandemic gains ground in the developing world, where many millions of people live under deprived conditions and have multiple health problems, with little access to basic health care.

As much current data about the pandemic come from wealthy and middle-income countries, the situation in developing countries will need to be very closely watched. The same virus that causes manageable disruption in affluent countries could have a devastating impact in many parts of the developing world.

Co-infection with HIV

The 2009 influenza pandemic is the first to occur since the emergence of HIV/AIDS. Early data from two countries suggest that people co-infected with H1N1 and HIV are not at increased risk of severe or fatal illness, provided these patients are receiving antiretroviral therapy. In most of these patients, illness caused by H1N1 has been mild, with full recovery.

If these preliminary findings are confirmed, this will be reassuring news for countries where infection with HIV is prevalent and treatment coverage with antiretroviral drugs is good.

On current estimates, around 33 million people are living with HIV/AIDS worldwide. Of these, WHO estimates that around 4 million were receiving antiretroviral therapy at the end of 2008.

http://www.who.int/csr/disease/swineflu/notes/h1n1_second_wave_20090828/en/index.html

The Associated Press reported that Britain and France received their first batches of swine flu vaccine “as governments begin to arm themselves against a widely expected second wave of the pandemic in the northern winter.” British and French health officials said the H1N1 vaccine should win licensing approval for distribution in their countries by October. Britain’s Department of Health said it received a first batch of 100,000 doses of swine flu vaccine from Baxter. France “has reserved 94 million doses of vaccine from four pharmaceutical companies and expects to have several million doses by mid-October when the vaccines are set to win market approval.

http://www.smh.com.au/world/britain-france-get-first-batches-of-swine-flu-vaccine-20090828-f1i2.html

The FDA announced that it issued an Emergency Use Authorization (EUA) that allows a 2009 H1N1 influenza virus test to be used to detect the virus in troops serving overseas. The EUA “allows the U.S. Department of Defense to distribute the H1N1 test to its qualified laboratories that have the required equipment and trained personnel to perform the test and interpret its results. An EUA authorizes the use of unapproved medical products or unapproved uses of approved medical products during a declared public health emergency.” FDA Commissioner of Food and Drugs Margaret A. Hamburg, M.D. commented, “The FDA worked quickly with the Defense Department to authorize the use of this test to better protect our troops. The test will aid in more rapid diagnosis of 2009 H1N1 influenza infections so that deployed troops can quickly begin appropriate medical treatment.” http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm180153.htm

The MMWR: August 28, 2009 / Vol. 58 / No. RR–10 includes:
2009 Pandemic Influenza A (H1N1) Virus Infections
Chicago, April–July 2009

On April 21, 2009, CDC reported the first cases of 2009 pandemic influenza A (H1N1) virus infection in the United States. On April 24, in response to those reports, the Chicago Department of Public Health established enhanced surveillance for 2009 pandemic influenza A (H1N1) virus infections. The first cases were identified on April 28. This report summarizes laboratory confirmed cases identified during April 24–July 25, and provides clinical and epidemiologic data for a subset of those cases

Use of Influenza A (H1N1) 2009 Monovalent Vaccine
Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009
This report provides recommendations by CDC’s Advisory Committee on Immunization Practices (ACIP) regarding the use of vaccine against infection with novel influenza A (H1N1) virus. Licensed vaccine is expected to be available by mid-October 2009. Highlights of these recommendations include 1) the identification of five general population target groups for initial focus of vaccination efforts (pregnant women, persons who live with or provide care for infants aged <6 months, health-care and emergency medical services personnel, children and young adults aged 6 months–24 years, and persons aged 25–64 years who have medical conditions that put them at higher risk for influenza-related complications), 2) establishment of a priority for a subset of persons within the initial target groups in the event that initial vaccine availability is unable to meet demand, and 3) guidance on use of vaccine in other adult population groups as vaccine availability increases.

http://www.cdc.gov/mmwr/

The WHO issued its revised position paper on measles vaccination making “vaccination of all children with two doses of measles vaccine as the standard for all national immunization programmes.” WHO said the second dose can be administered through routine services or given periodically through mass vaccination campaigns to defined age groups. In 2007, WHO estimated that 82% of the world’s children received one dose of measles vaccine by their first birthday and about 197,000 people, mostly children under the age of five, died from measles. “To eliminate measles, countries need to reach at least 95% nationwide coverage with two doses of measles vaccine. To achieve reduction of measles mortality, vaccination coverage should reach at least 90% at the national level and 80% in each district,” WHO said.

WHO position paper on measles vaccine [pdf 724kb]
http://www.who.int/immunization/newsroom/WHO_position_paper_measles/en/index.html

The Bill & Melinda Gates Foundation’s Global Health Program announced that Dr. Stefano Bertozzi will join as HIV director effective 31 August 2009. Dr. Bertozzi “will lead a team that manages the foundation’s portfolio of grants in HIV vaccine development, biomedical prevention research, diagnostics, development and resistance monitoring, and strategies for introduction and scaling-up of the foundation, said, “Stefano brings a wealth of experience to his new role. His intimate knowledge of the medicine, science, economics and policy of HIV will help make this important portfolio have the most impact.” Gates said that Dr. Bertozzi worked with the foundation in his previous roles at UNAIDS, the World Health Organization (WHO) and the World Bank. For the last 11 years, he has been with the National Institute of Public Health (INSP) in Mexico. http://www.gatesfoundation.org/press-releases/Pages/dr-stefano-bertozzi-leading-hiv-vaccine-team-090826.aspx

Editor’s Note: We do not endorse or otherwise have any relationship to companies that produce market analysis and similar reports, but occasionally provide useful information where relevant to the vaccine enterprise and our work in vaccine ethics and policy]

Research and Markets: China Vaccine Industry Report, 2008-2009: Largest Producer in the World with Annual Production of One Billion Person-Portions

“In the past decade, the Chinese vaccine market tripled in scale. China has already become the world’s largest vaccine producer and now has 28 vaccine companies, ranking NO.1 around the globe. It can produce one billion person-portions annually, besides, varieties and quantity it also ranks the top in the world.

“Output of common vaccine reaches 500 million person-portions such as HBV vaccine, measles vaccine, etc. Fully planned immunization has been realized.

“Compared to developed countries, expenses of China on vaccine and diseases treatment are relatively low; therefore, China will attach great importance to vaccine industry development and takes it as the key of healthcare and bio-technology industry.    “The Development Strategy of China Bio-technology Industry has rendered the development of secure new types of vaccines as priority; in the meantime, the Chinese government has employed preferential taxation policy to this industry. In consequence, the vaccine industry will become a high-tech sector with great potential in China’s bio-technology field. It is forecasted that China’s vaccine market scale will approximate RMB8 billion in 2020, with an annual growth rate of 15%, far above world’s level 10%…”

(BUSINESS WIRE, 25 August 2009)

JAMA
Vol. 302 No. 8, pp. 825-914, August 26, 2009
http://jama.ama-assn.org/current.dtl

Commentaries
Setting Priorities for Patient Safety: Ethics, Accountability, and Public Engagement
Peter J. Pronovost; Ruth R. Faden

[First 150 words per JAMA convention]
Patients continue to experience preventable harms. As a result, policy makers, physicians, and members of the public have intensified their efforts to improve patient safety. The Joint Commission publishes National Patient Safety Goals, the National Quality Forum recommends safe practices, the Centers for Medicare & Medicaid Services (CMS) will not pay for certain preventable complications, and health care organizations are taking action to reduce preventable harm. Although these actions are welcome, they raise ethical questions about selecting health care areas or patient populations for improvement efforts. In this Commentary, we explore the contentious issue of deciding what warrants a priority in patient safety and offer strategies to guide further discussion, policy, and research.

When patient safety garnered the attention of policy makers with the 1999 To Err Is Human1 report, resources were scarce, harm was ubiquitous, and the…

Author Affiliations: Departments of Anesthesiology and Critical Care Medicine, and Surgery and Bloomberg School of Public Health, Department of Health Policy and Management, The Johns Hopkins University School of Medicine (Dr Pronovost) and The Johns Hopkins Berman Institute of Bioethics (Dr Faden), Baltimore, Maryland.

JAMA
Vol. 302 No. 8, pp. 825-914, August 26, 2009
http://jama.ama-assn.org/current.dtl

Editorial
Addressing the Global Disease Burden of Typhoid Fever
Zulfiqar A. Bhutta; John Threlfall

[First 150 words per JAMA convention]
Salmonella ser Typhi infections are widely recognized as a major cause of morbidity globally, with an estimated 21 million cases and between 200 000 and 600 000 deaths annually.1-2 The divergent estimates likely represent differences in methods used for assessing age-specific burden of typhoid and attributable mortality.3 In some parts of the world, notably South Asia,4 young children represent a subgroup with the highest burden of typhoid and also may have disproportionately high rates of morbidity and complications.5 The report by Lynch et al6 in this issue of JAMA summarizes current knowledge about cases of typhoid fever in the United States and highlights the role of international travel, the need for broader immunization practices, and concerns regarding increases in antibacterial resistance.

In addition to the disease burden and mortality, emergence of drug resistance among S Typhi and Salmonella ser Paratyphi, which causes a…”

New England Journal of Medicine
Volume 361 — August 27, 2009 — Number 9
http://content.nejm.org/current.shtml

Perspective
H1N1 Influenza, Public Health Preparedness, and Health Care Reform
N. Lurie

In December 2009, the Department of Health and Human Services will present to Congress its first-ever national health security strategy, outlining high-priority activities and areas of investment for strengthening the capability of the United States to prepare for, respond to, and recover from large-scale public health emergencies. Fortunately, the strategy is being developed in parallel with a national debate over health care reform, since national health security will not be achievable without key elements of reform.

These elements include an effective focus on prevention and wellness, universal access to needed care, widespread deployment of health information technology, changes in the organization of and payment for care, and research on comparative effectiveness.

A hazard equation that informs many approaches to preparedness makes it clear that risk can be reduced by mitigating vulnerabilities and hazards and increasing resilience.1 People who are vulnerable because they are poor or have underlying health conditions suffer disproportionately in nearly all emergencies.1 The people hit hardest by Hurricane Katrina, for instance, were those with the highest burden of chronic disease, many of whom could not be evacuated because they had physical disabilities or required ongoing care.2 Responders were caught off guard by the extent of the population’s needs. Although many lessons from Katrina were heeded after Hurricane Ike in 2008, a high prevalence of obesity among Ike’s victims strained the systems responsible for evacuation and provision of shelter.

As a result, some relief organizations now require morbidly obese people to be served in special-needs shelters, a requirement that puts a strain on those resources as well. But if the investments in prevention and wellness that are envisioned in a reformed health care system — including payment for preventive care, aggressive secondary prevention, and population-level interventions to prevent chronic disease and its complications — achieve their aims, they will increase the population’s resilience by reducing key vulnerabilities, including those associated with obesity, chronic diseases, and illnesses that are preventable with vaccines.

Early detection of a new infectious disease — and potentially the survival of those who are infected — requires that sick people have access to the health care system and receive early treatment. Delays in seeking care can lead to delays in the recognition and control of an epidemic and in the treatment of patients. Indeed, experts have hypothesized that one reason the mortality associated with the current epidemic of swine-origin influenza A (H1N1) virus (S-OIV) was so high in Mexico is that many people delayed seeking care, in part because of its cost.3 In the United States, lack of health insurance is a key reason for delays in seeking care; health care reform that results in universal coverage would facilitate earlier detection of new diseases, enable disease-control efforts to be instituted, and alleviate the population’s vulnerability that is attributable to delayed care.

During a large-scale health emergency, emergency care must be available to seriously ill or injured patients. Without substantial changes in policies and procedures, overcrowded emergency departments and inefficient hospitals will struggle to handle a surge of patients who are acutely ill, as well as those who are worried but only mildly ill. The emergency departments in New York City experienced overcrowding in the spring of 2009 because of H1N1 influenza. Yet studies repeatedly suggest that one half to two thirds of emergency department visits are potentially avoidable if there is timely access to high-quality primary care.4 In some cities, the lack of communication between emergency transportation systems and hospitals means that patients are taken to emergency departments that are too busy or too poorly equipped to care for them. Implementing the recommendations of the Institute of Medicine for revamping the emergency medical services system as part of health care reform will be critical to alleviating overcrowding in emergency departments, improving turnover time, and enhancing the capacity of emergency departments to handle a surge of acutely ill or injured patients.

Investments in interoperable health information technology (HIT) form one of the cornerstones of health care reform. After Hurricane Katrina, the lack of access to medical records was a major impediment to caring for most displaced, chronically ill persons; the records of those who received care through the Department of Veterans Affairs, however, were accessible anywhere in the country. Portable, interoperable HIT will be essential for efficiently and safely caring for displaced populations during a health emergency.

With appropriate planning and standards, HIT can also play a key role in detecting and monitoring disease outbreaks. Routine, automated reporting of diagnoses to health departments by primary care practices, emergency departments, and laboratories can provide early evidence of an impending epidemic. Such monitoring has proved useful in determining whether a report of a single case might be accompanied by spikes in the use of health care services, signaling that many people are ill. Such a system was used recently by the New York City health department and others to determine whether large numbers of people were ill when a cluster of cases of H1N1 influenza was identified in a school and to monitor the epidemic.

A key challenge facing public health officials who are planning responses to a potentially more severe H1N1 influenza epidemic this fall is finding a way to quickly link information regarding who is vaccinated to information about the subsequent use of health care services by these people. Such linking will be essential for detecting and interpreting reports of adverse events after vaccination and determining the effectiveness of vaccines in preventing illness. Whereas some countries with universal health care systems can readily gather and use such information, the fact that not all Americans are accounted for in our system and the lack of HIT make it impossible to do so in most of the United States.

In the event of a large-scale health emergency such as an influenza pandemic, the health care system will experience unprecedented demand. Although much care can be provided outside hospital settings, intensive-care resources will be in particularly short supply. Determining how to retain — and pay for — the capacity to “surge” in such an event is a critical aspect of health preparedness; it is particularly challenging, however, because one way to achieve the cost-containment goal of health care reform is to shift care from expensive inpatient settings to less expensive outpatient settings. New approaches, including self-triage guidelines, remote monitoring devices, and telemedicine, support such shifts in the delivery of care. Research suggests that building excess emergency-department and inpatient capacity as a sort of insurance policy may not be a sound approach and will only increase health care expenditures: if capacity is there, it will be used for other, nonemergency care. Unfortunately, we have not yet found the right payment policies to ensure that hospitals will be able to defer elective procedures and discharge patients who are less severely ill in order to make space for those who are more acutely ill.

Currently, we are far from allocating our resources with maximum efficiency, even in the absence of a large-scale emergency. For example, real-time electronic reporting of available bed capacity is not widespread, despite several years of investment in hospital preparedness. Hospitals still have patients who might be better served with a less intensive level of care, remote monitoring and telehealth technologies are not yet widely deployed, and our surveillance systems are lacking in timeliness and coverage.

Finally, the scientific basis for the real-world application of preparedness measures is underdeveloped. For example, are some modes of public communication in a health emergency or some social-distancing strategies to prevent the spread of disease better than others? Comparative-effectiveness research, a cornerstone of the Obama administration’s approach to health care reform, will be essential for gathering evidence to support particular preparedness measures and for ensuring the creation of a maximally efficient system.

In summary, a U.S. health security strategy will need to build on, and take full advantage of, core components of a reformed health care system. With the right approach, reform could facilitate vast improvements in our ability to respond to and recover from large-scale health emergencies.

No potential conflict of interest relevant to this article was reported.

Source Information

From RAND Health, Arlington, VA. After writing this article, Dr. Lurie was named Assistant Secretary for Preparedness and Response, Department of Health and Human Services.

References

Keim ME, Giannone P. Disaster preparedness. In: Cittone GR, ed. Disaster medicine. St. Louis: Mosby, 2006:164-73.

Kessler RC, Hurricane Katrina Community Advisory Group. Hurricane Katrina’s impact on the care of survivors with chronic medical conditions. J Gen Intern Med 2007;22:1225-1230. [CrossRef][Web of Science][Medline]

Lacey M, Malkin E. First flu death provides clues to Mexico toll. New York Times. April 30, 2009.

Oster A, Bindman AB. Emergency department visits for ambulatory care sensitive conditions: insights into preventable hospitalizations. Med Care 2003;41:198-207. [CrossRef][Web of Science][Medline]

Vaccine
Volume 27, Issue 41, Pages 5543-5708 (18 September 2009)
http://www.sciencedirect.com/science/journal/0264410X

Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine
Pages 5612-5619
Ali Rowhani-Rahbar, Constance Mao, James P. Hughes, Frances B. Alvarez, Janine T. Bryan, Stephen E. Hawes, Noel S. Weiss, Laura A. Koutsky

Abstract
We conducted an extended follow-up study (March 2006–May 2008) to assess the longer term efficacy of a prophylactic monovalent human papillomavirus (HPV) type 16 L1 virus-like particle vaccine in women (n = 290) who had enrolled in a randomized controlled trial of this vaccine (October 1998–November 1999) in Seattle and remained HPV-16 DNA negative during the course of that trial. During the extended follow-up period, in the per-protocol susceptible population, none of the vaccine recipients was found to be infected with HPV-16 or developed HPV-16-related cervical lesions; among placebo recipients, 6 women were found to be infected with HPV-16 (vaccine efficacy [VE] = 100%; 95% confidence interval [CI]: 29–100%) and 3 women developed HPV-16-related cervical lesions (VE = 100%; 95% CI: <0–100%). Approximately 86% of vaccine recipients remained HPV-16 competitive Luminex immunoassay seropositive at an average of 8.5 years of follow-up. During the combined original trial and extended follow-up period, in the intention-to-treat population, 20 and 22 women developed any cervical lesion regardless of HPV type among the vaccine and placebo recipients, respectively (VE = 15%; 95% CI: <0–56%). The results suggest that this monovalent HPV-16 vaccine remains efficacious through 8.5 years after its administration.

The following Call to Action was issued on 17 August 2009:

WHO, IFRC, UNSIC, OCHA and UNICEF, prompted by the humanitarian imperative, will work with partners such as the Red Cross and Red Crescent Societies, NGOs and civil society to support governments and communities to reduce the impact from the pandemic (H1N1) 2009.

Key principles

 The H1N1 influenza pandemic is spreading rapidly, but its future evolution cannot be predicted. Most data about the pandemic have been acquired in countries with well-functioning health services.

 Worldwide, the overwhelming majority of cases continue to experience mild symptoms and recover fully, without the need for medical care.

 Pregnant women and people with underlying medical conditions are known to be at increased risk of severe and sometimes fatal illness.

 Although viruses from all outbreak sites are virtually identical, the impact of the pandemic is likely to be more severe in countries with weak health systems, poor health status, and limited resources.

 In these settings, the pandemic can divert scarce resources and strain already weak health services.

 Countries where health services are overburdened by diseases, such as HIV/AIDS, tuberculosis, and malaria, will have great difficulty managing the surge of cases seen when pandemic influenza spreads.

To reduce the impact of the pandemic:

1. Identify populations at increased risk of disease and death:

 Identify and prioritize high-risk groups and areas for increased disease (crowded or closed settings) and death (those with underlying illness, pregnancy or poor access to health care).

2. Reduce death by treating acute respiratory illness and pneumonia:

 Train, supervise and ensure health care workers, including community health workers, can identify, triage, classify and treat acute respiratory illness and pneumonia in line with national protocols.

 Governments with support by humanitarian partners and donor governments plan for an additional 30 percent buffer stock of medical supplies to treat pneumonia such as paracetamol, antibiotics, and oxygen, at the outpatient and inpatient levels.

 Inform and educate the community about home-care of symptoms of non-severe influenza-like illness including diarrhoea and dehydratation. Include advice about voluntary separation of the sick and when to seek health care.

 If antiviral therapy is available, ensure use for treatment of severe influenza.

3. Reduce spread of the disease:

 Prepare and disseminate risk communication messages by health care workers, volunteers and the community on individual and societal prevention measures in line with national policies and local risk assessment. Risk communication should promote home-care of mild cases; reduced time in crowded settings, especially by high-risk groups; and respiratory etiquette and hand hygiene.

 Map and train social mobilization networks to promote prevention measures when activated.

 Identify target groups to receive first doses of vaccination and advocate for their access.

 Develop operational plans for mass vaccination, when vaccine is available.

4. Continue critical services and plan for the worst:

 Review, revise or create business continuity plans for all key organizations to continue critical operations.

 Revise, reactivate or create contingency plans at the country and local levels that prioritize continuation of critical health and other essential services as part of a whole of society approach. Ensure a scenario for a severe pandemic building on existing multi-hazard multi-sector contingency plans and engage national disaster management organizations.

 Ensure at least 8 to 12 weeks of buffer stocks of essential medicines to continue treating priority conditions (i.e. diarrhoea, malaria, malnutrition, HIV and TB) in the community and in health facilities.

5. Plan and coordinate efforts

 Incorporate pandemic activities into existing coordination mechanisms such as the Health Cluster/health sector for coordination, resource mapping and mobilization, assessments and gaps, information management, joint strategies, contingency planning, and training.

 No one agency can provide all of priority interventions. Instead they should be coordinated by building on capacities and comparative advantages of each partner

The WHO has continued its series of Briefing Notes, with three issued since early August 2009:

Pandemic (H1N1) 2009 briefing note 6: Safety of pandemic vaccines http://www.who.int/csr/disease/swineflu/notes/h1n1_safety_vaccines_20090805/en/index.html

Pandemic (H1N1) 2009 briefing note 7: Pandemic influenza vaccine manufacturing process and timeline http://www.who.int/csr/disease/swineflu/notes/h1n1_vaccine_20090806/en/index.html

Pandemic (H1N1) 2009 briefing note 8: Recommended use of antivirals http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_20090820/en/index.html

The Weekly Epidemiological Record (WER) for 21 August 2009, vol. 84, 34 (pp 341–348) includes: Mathematical modelling of the pandemic H1N1 2009. http://www.who.int/wer/2009/wer8434.pdf

The New York State Health Department “is requiring tens of thousands of health care workers across the state to be vaccinated for flu, amid fears that swine flu will return in the fall.” The new regulation “affects workers at hospitals, in home health care agencies and in hospice care, but, because of a technicality in state law, not in nursing homes.” The regulation raised protest Tuesday from New York’s largest health care union, 1199 S.E.I.U. United Healthcare Workers East, whose president, George Gresham, said that the policy was “completely unprecedented” and could become punitive if the religious or cultural beliefs of workers prevented them from being vaccinated. Mr. Gresham commented, “Health care workers on the front lines of providing care deserve the dignity and respect of thoughtful consideration before a regulation like this can just be rushed through and put into effect,”. The new regulation requires vaccination against seasonal flu and the H1N1 virus, and would affect workers and volunteers who come into direct contact with patients, including nurses, doctors and aides, and even nonmedical staff members like food service workers if they enter a patient’s room, a Health Department spokeswoman said.

(NY Times, 18 August 2009) http://www.nytimes.com/2009/08/19/health/policy/19swine.html?_r=1

The U.S. Food and Drug Administration announced approval of Hiberix, a Haemophilus influenzae Type b (Hib) vaccine, as a booster dose for children 15 months through 4 years old. Hiberix is manufactured by GlaxoSmithKline. The action “addresses a nationwide shortage in the U.S. of Hib vaccine began in December 2007 due to a voluntary recall by the manufacturer and subsequent production suspension of PedvaxHIB and COMVAX, two of four vaccines licensed in the United States for primary and booster immunization against invasive disease due to Hib. Both PedvaxHIB and COMVAX vaccines are manufactured by Merck & Co. Inc. (Whitehouse Station, N.J.).

This shortage resulted in a recommendation by the U.S. Centers for Disease Control and Prevention to temporarily defer the Hib vaccine booster dose for children who were not at high risk for infection, until the vaccine supply could be restored. This deferral was in effect from Dec. 18, 2007, through June 25, 2009.”  Karen Midthun, M.D., acting director of the FDA’s Center for Biologics Evaluation and Research, said, “The FDA approved Hiberix under the agency’s accelerated approval pathway. This approval will provide an additional safe and effective vaccine to help ensure that there is an adequate Hib vaccine supply during necessary catch-up vaccinations.” http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm179533.htm

GAVI will provide funding worth US$165 million which “paves the way for the introduction of pentavalent five-in-one vaccine in India, where some 27 million children are born each year. This is the first phase of a national roll-out which will start in 10 states. More than 18 million children in India will be immunised.” The pentavalent vaccine protects against diphtheria, tetanus, pertussis (whooping cough), hepatitis B, and Haemophilus influenzae type b. GAVI noted that the introduction of this pentavalent vaccine in India “will mean that now more than 90% of the world’s poorest children will be vaccinated against Hib.” India Health Minister Gulam Nabi Azad commented, “The introduction of the pentavalent vaccine in India is a critical step in our government’s efforts to protect all Indian children from deadly diseases. We are glad to be working with the GAVI Alliance to turn this long-held vision into a reality for millions of families. I am extremely thankful to GAVI for assistance given for pentavalent vaccine.”

http://www.gavialliance.org/media_centre/press_releases/2009_08_11_india_pentavalent.php

The TuBerculosis Vaccine Initiative (TBVI) said it received a US$3 million grant for a three-year term from the Bill & Melinda Gates Foundation. This grant enables the nonprofit organization “to strengthen its fundraising and communication activities in order to increase awareness and support for tuberculosis (TB) vaccine research and raise funds for the development of safer and more effective vaccines.”  Full media release at: TuBerculosis Vaccine Initiative.

PATH was selected to receive the 2009 Conrad N. Hilton Humanitarian Prize, which includes an unrestricted award of US$1.5 million. The Conrad N. Hilton Foundation “presents the annual award, the world’s largest humanitarian prize, to an organization that is significantly alleviating human suffering.” The prize will be presented on September 21 in Washington, DC, with keynote speaker Muhammad Yunus, who is a Nobel Peace Prize laureate, founder of the Grameen Bank, and former Hilton Prize juror. Steven M. Hilton, president and CEO of the Hilton Foundation, said, “Bringing new ideas and technologies to the toughest global health challenges and scaling them up at low prices, often hand-in-hand with the private sector, PATH is having a profound impact on the health and quality of life of millions of men, women, and children around the world,” said. Dr. Christopher J. Elias, PATH’s president and CEO, commented, “PATH is
honored to be selected for the prestigious Hilton Humanitarian Prize. We will use the Prize funds as innovation capital to support new initiatives in areas we’ve identified as critical to PATH’s mission: accelerating innovation in product development and introduction; bringing to scale essential health solutions and programs; and expanding our field presence, especially in Africa.”

JAMA
Vol. 302 No. 7, pp. 715-E1, August 19, 2009
http://jama.ama-assn.org/current.dtl

Original Contribution
Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine
Barbara A. Slade, MD, MS; Laura Leidel, RN, FNP-C, MPH; Claudia Vellozzi, MD, MPH; Emily Jane Woo, MD, MPH; Wei Hua, MD, PhD; Andrea Sutherland, MD, MSc, MPH; Hector S. Izurieta, MD, MPH; Robert Ball, MD, MPH; Nancy Miller, MD; M. Miles Braun, MD, MPH; Lauri E. Markowitz, MD; John Iskander, MD

JAMA. 2009; 302(7):750-757.

Context  In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years.

Objective  To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV.

Design, Setting, and Participants  Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting.

Main Outcome Measures  Numbers of reported AEFIs, reporting rates (reports per 100 000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates.

Results  VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100 000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100 000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods.

Conclusions  Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.

Author Affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Slade, Vellozzi, Markowitz, and Iskander and Ms Leidel); US Food and Drug Administration, Washington, DC (Drs Woo, Hua, Sutherland, Izurieta, Ball, Miller, and Braun).

JAMA
Vol. 302 No. 7, pp. 715-E1, August 19, 2009
http://jama.ama-assn.org/current.dtl

Special Communication
Marketing HPV Vaccine: Implications for Adolescent Health and Medical Professionalism
Sheila M. Rothman, PhD; David J. Rothman, PhD

JAMA. 2009;302(7):781-786.

[Abstract]
The new vaccine against 4 types of human papillomavirus (HPV), Gardasil, like other immunizations appears to be a cost-effective intervention with the potential to enhance both adolescent health and the quality of their adult lives. However, the messages and the methods by which the vaccine was marketed present important challenges to physician practice and medical professionalism. By making the vaccine’s target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to adolescents was maximized, and the subpopulations most at risk practically ignored. The vaccine manufacturer also provided educational grants to professional medical associations (PMAs) concerned with adolescent and women’s health and oncology. The funding encouraged many PMAs to create educational programs and product-specific speakers’ bureaus to promote vaccine use. However, much of the material did not address the full complexity of the issues surrounding the vaccine and did not provide balanced recommendations on risks and benefits. As important and appropriate as it is for PMAs to advocate for vaccination as a public good, their recommendations must be consistent with appropriate and cost-effective use.

JAMA
Vol. 302 No. 7, pp. 715-E1, August 19, 2009
http://jama.ama-assn.org/current.dtl

Editorial
The Risks and Benefits of HPV Vaccination
Charlotte Haug

[First 125 words per JAMA convention]
When do physicians know enough about the beneficial effects of a new medical intervention to start recommending or using it? When is the available information about harmful adverse effects sufficient to conclude that the risks outweigh the potential benefits? If in doubt, should physicians err on the side of caution or on the side of hope? These questions are at the core of all medical decision making. It is a complicated process because medical knowledge is typically incomplete and ambiguous. It is especially complex to make decisions about whether to use drugs that may prevent disease in the future, particularly when these drugs are given to otherwise healthy individuals. Vaccines are examples of such drugs, and the human papillomavirus (HPV) vaccine is a case in point.

JAMA
Vol. 302 No. 6, pp. 599-704, August 12, 2009

Commentary
Understanding Influenza Backward

David M. Morens, MD; Jeffery K. Taubenberger, MD, PhD
JAMA. 2009;302(6):679-680.

[First 150 words per JAMA convention]
The novel 2009 influenza A(H1N1) pandemic virus has been an unexpected trigger for pandemic preparedness plans in the United States and elsewhere.1 It is appropriate to ask how the novel virus might behave epidemiologically in coming months, including the possibility of multiple recurrences or “waves.” Spring circulation of the novel virus in the Northern Hemisphere at the end of the 2008-2009 influenza season inevitably has led to comparisons with events in 1918-1919, which in some settings were preceded and followed by outbreaks of respiratory illnesses. Some also believe that the 1918 pandemic began with a premonitory “herald wave,” a term related to an old hypothesis, which influenza and dengue fever appeared to have supported, that as new viruses begin to circulate in human populations they inevitably acquire mutations that increase transmissibility and virulence. Evidence for unusual influenza activity in the years . . .

Author Affiliations: Office of the Director (Dr Morens) and Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases (Dr Taubenberger), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

Journal of Infectious Diseases
1 September 2009  Volume 200, Number 5

Editorial Commentaries
Polio: Measuring the Protection That Matters Most
Paul E. M. Fine

MAJOR ARTICLE
Mucosal Immunity after Vaccination with Monovalent and Trivalent Oral Poliovirus Vaccine in India

Nicholas C. Grassly,1; Hamid Jafari,2; Sunil Bahl,2; Sunita Durrani,2; Jay Wenger,2,a
Roland W. Sutter,3 and R. Bruce Aylward3
1Department of Infectious Disease Epidemiology, Imperial College London, United Kingdom; 2National Polio Surveillance Project, World Health Organization–Government of India, New Delhi, India; 3Global Polio Eradication Initiative, World Health Organization, Geneva, Switzerland

Background.Persistent wild‐poliovirus transmission, particularly in India, has raised questions about the degree of mucosal immunity induced by oral poliovirus vaccine (OPV) in tropical countries.

Methods.Excretion of vaccine poliovirus after challenge with OPV was measured in stool samples collected from children identified by the acute flaccid paralysis surveillance program in India during 2005–2007. The effectiveness of trivalent and monovalent OPV against excretion of each poliovirus type was estimated.

Results.Vaccine poliovirus was isolated from 4994 (5.2%) of 96,641 children with 2 stool samples. The relative odds of excreting challenge poliovirus among children with 5 reported previous doses of trivalent OPV compared with 0 previous doses was 0.24 (95% confidence interval [CI], 0.12–0.45), 0.08 (95% CI, 0.04–0.14), and 0.40 (95% CI, 0.19–0.85) for serotypes 1, 2, and 3, respectively, but the relative odds increased to 0.62 (95% CI, 0.44–0.88), 0.44 (95% CI, 0.20–0.99), and 0.66 (95% CI, 0.41–1.06), respectively, in the northern states of Uttar Pradesh and Bihar. In these 2 states, the relative odds of excretion of serotype 1 was 0.32 (95% CI, 0.26–0.41) after 5 doses of type 1 monovalent OPV.

Conclusions.The mucosal immunity induced by OPV in India varies by location, serotype, and vaccine formulation. These findings have implications for global eradication and the potential role played by inactivated vaccine in this setting.

The Lancet
Aug 08, 2009   Volume 374  Number 9688  Pages 427 – 500

Comment
Pandemic H1N1 infection in pregnant women in the USA
Punam Mangtani, Tippi K Mak, Dina Pfeifer

“Although most infections with the current pandemic H1N1 virus have been self-limited, the risk of influenza complications is higher in some subpopulations. More than 70% of US admissions to hospital for H1N1 infection so far have been for individuals with underlying medical conditions.1 Pregnant women had an increased risk of influenza complications in two past pandemics (1918–19 and 1957–58). For instance, the Confidential Enquiries into Maternal Deaths in England and Wales noted 28 maternal deaths due to clinical influenza in 1957 (18 expected, on the basis of mortality rates in non-pregnant women aged 15–45 years).”

H1N1 2009 influenza virus infection during pregnancy in the USA
Denise J Jamieson MD a, Margaret A Honein PhD b, Sonja A Rasmussen MD b, Jennifer L Williams MSN b, David L Swerdlow MD c, Matthew S Biggerstaff MPH c, Stephen Lindstrom PhD c, Janice K Louie MD e, Cara M Christ MD f, Susan R Bohm MS g, Vincent P Fonseca MD h, Kathleen A Ritger MD i, Daniel J Kuhles MD j, Paula Eggers RN k, Hollianne Bruce MPH l, Heidi A Davidson MPH m, Emily Lutterloh MD d n, Meghan L Harris MPH o, Colleen Burke MSN p, Noelle Cocoros MPH q, Lyn Finelli DrPH c, Kitty F MacFarlane CNM a, Bo Shu MD c, Sonja J Olsen PhD c, the Novel Influenza A (H1N1) Pregnancy Working Group‡

Summary
Background

Pandemic H1N1 2009 influenza virus has been identified as the cause of a widespread outbreak of febrile respiratory infection in the USA and worldwide. We summarised cases of infection with pandemic H1N1 virus in pregnant women identified in the USA during the first month of the present outbreak, and deaths associated with this virus during the first 2 months of the outbreak.

Methods
After initial reports of infection in pregnant women, the US Centers for Disease Control and Prevention (CDC) began systematically collecting additional information about cases and deaths in pregnant women in the USA with pandemic H1N1 virus infection as part of enhanced surveillance. A confirmed case was defined as an acute respiratory illness with laboratory-confirmed pandemic H1N1 virus infection by real-time reverse-transcriptase PCR or viral culture; a probable case was defined as a person with an acute febrile respiratory illness who was positive for influenza A, but negative for H1 and H3. We used population estimates derived from the 2007 census data to calculate rates of admission to hospital and illness.

Findings
From April 15 to May 18, 2009, 34 confirmed or probable cases of pandemic H1N1 in pregnant women were reported to CDC from 13 states. 11 (32%) women were admitted to hospital. The estimated rate of admission for pandemic H1N1 influenza virus infection in pregnant women during the first month of the outbreak was higher than it was in the general population (0·32 per 100 000 pregnant women, 95% CI 0·13—0·52 vs 0·076 per 100 000 population at risk, 95% CI 0·07—0·09). Between April 15 and June 16, 2009, six deaths in pregnant women were reported to the CDC; all were in women who had developed pneumonia and subsequent acute respiratory distress syndrome requiring mechanical ventilation.

Interpretation
Pregnant women might be at increased risk for complications from pandemic H1N1 virus infection. These data lend support to the present recommendation to promptly treat pregnant women with H1N1 influenza virus infection with anti-influenza drugs.

Funding: US CDC.

The Lancet Infectious Disease
Sep 2009  Volume 9  Number 9   Pages 521 – 582
http://www.thelancet.com/journals/laninf/issue/current

Review
Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis

Original Text
Jane Burch PhD a, Mark Corbett MSc a, Christian Stock MSc a, Prof Karl Nicholson MD b, Alex J Elliot PhD c, Steven Duffy PgDip a, Marie Westwood PhD a, Stephen Palmer MSc d, Prof Lesley Stewart PhD a

Summary

In publicly funded health systems with finite resources, management decisions are based on assessments of clinical effectiveness and cost-effectiveness. The UK National Institute for Health and Clinical Excellence commissioned a systematic review to inform their 2009 update to guidance on the use of antiviral drugs for the treatment of influenza. We searched databases for studies of the use of neuraminidase inhibitors for the treatment of seasonal influenza. We present the results for healthy adults (ie, adults without known comorbidities) and people at-risk of influenza-related complications. There was an overall reduction in the median time to symptom alleviation in healthy adults by 0·57 days (95% CI −1·07 to −0·08; p=0·02; 2701 individuals) with zanamivir, and 0·55 days (95% CI −0·96 to −0·14; p=0·008; 1410 individuals) with oseltamivir. In those at risk, the median time to symptom alleviation was reduced by 0·98 days (95% CI −1·84 to −0·11; p=0·03; 1252 individuals) with zanamivir, and 0·74 days (95% CI −1·51 to 0·02; p=0·06; 1472 individuals) with oseltamivir. Little information was available on the incidence of complications. In view of the advantages and disadvantages of different management strategies for controlling seasonal influenza in healthy adults recommending the use of antiviral drugs for the treatment of people presenting with symptoms is unlikely to be the most appropriate course of action.

The Lancet Infectious Disease
Sep 2009  Volume 9  Number 9   Pages 521 – 582
http://www.thelancet.com/journals/laninf/issue/current

Review
Burden of disease and circulating serotypes of rotavirus infection in sub-Saharan Africa: systematic review and meta-analysis

Original Text

Elisabeth Sanchez-Padilla MD a, Rebecca F Grais PhD a, Philippe J Guerin MD a, Andrew D Steele PhD b, Marie-Eve Burny MD c, Francisco J Luquero MD a d

Summary

Two new rotavirus vaccines have recently been licensed in many countries. However, their efficacy has only been shown against certain serotypes commonly circulating in Europe, North America, and Latin America, but thought to be globally important. To assess the potential impact of these vaccines in sub-Saharan Africa, where rotavirus mortality is high, knowledge of prevalent types is essential because an effective rotavirus vaccine is needed to protect against prevailing serotypes in the community. We did two systematic reviews and two meta-analyses of the most recent published data on the burden of rotavirus disease in children aged under 5 years and rotavirus serotypes circulating in countries in sub-Saharan Africa. Eligible studies were selected from PubMed/Medline, Cochrane Library, EmBase, LILACS, Academic Search Premier, Biological Abstracts, ISI Web of Science, and the African Index Medicus. Depending on the heterogeneity, DerSimonian—Laird random-effects or fixed-effects models were used for meta-analyses. Geographical variability in rotavirus burden within countries in sub-Saharan Africa is substantial, and most countries lack information on rotavirus epidemiology. We estimated that annual mortality for this region was 243·3 (95% CI 187·6—301·7) deaths per 100 000 under 5 years (ie, a total of 300 000 children die of rotavirus infection in this region each year). The most common G type detected was G1 (34·9%), followed by G2 (9·1%), and G3 (8·6%). The most common P types detected were P[8] (35·5%) and P[6] (27·5%). Accurate information should be collected from surveillance based on standardised methods in these countries to obtain comparable data on the burden of disease and the circulating strains to assess the potential impact of vaccine introduction.

Nature
Volume 460 Number 7258 pp933-1050  (13 August 2009)
http://www.nature.com/nature/journal/v460/n7255/

Books and Arts
Leading the fight against smallpox p954

John Carmody reviews Smallpox: The Death of a Disease by D. A. Henderson
Donald Henderson directed the World Health Organization’s effort to eradicate the variola virus. His memoir is a lesson in managing complex projects and personalities, says John Carmody.

Nature
Volume 460 Number 7258 pp933-1050  (13 August 2009)
http://www.nature.com/nature/journal/v460/n7255/

Letter
In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses

Yasushi Itoh1, Kyoko Shinya2, Maki Kiso3, Tokiko Watanabe4, Yoshihiro Sakoda5, Masato Hatta4, Yukiko Muramoto6, Daisuke Tamura3, Yuko Sakai-Tagawa3, Takeshi Noda7, Saori Sakabe3, Masaki Imai4, Yasuko Hatta4, Shinji Watanabe4, Chengjun Li4, Shinya Yamada3, Ken Fujii3, Shin Murakami3, Hirotaka Imai3, Satoshi Kakugawa3, Mutsumi Ito3, Ryo Takano3, Kiyoko Iwatsuki-Horimoto3, Masayuki Shimojima3, Taisuke Horimoto3, Hideo Goto3, Kei Takahashi3, Akiko Makino2, Hirohito Ishigaki1, Misako Nakayama1, Masatoshi Okamatsu5, Kazuo Takahashi8, David Warshauer9, Peter A. Shult9, Reiko Saito10, Hiroshi Suzuki10, Yousuke Furuta11, Makoto Yamashita12, Keiko Mitamura13, Kunio Nakano13, Morio Nakamura13, Rebecca Brockman-Schneider14, Hiroshi Mitamura15, Masahiko Yamazaki16, Norio Sugaya17, M. Suresh4, Makoto Ozawa4,7, Gabriele Neumann4, James Gern14, Hiroshi Kida5, Kazumasa Ogasawara1 & Yoshihiro Kawaoka2,3,4,6,7,18

Correspondence to: Yoshihiro Kawaoka2,3,4,6,7,18 Correspondence and requests for materials should be addressed to Y.K. (Email: kawaokay@svm.vetmed.wisc.edu).

Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses1. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.

New England Journal of Medicine
Volume 361 — August 13, 2009 — Number 7

Original Articles
Pneumonia and Respiratory Failure from Swine-Origin Influenza A (H1N1) in Mexico
R. Perez-Padilla and Others

ABSTRACT
Background In late March 2009, an outbreak of a respiratory illness later proved to be caused by novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico. We describe the clinical and epidemiologic characteristics of persons hospitalized for pneumonia at the national tertiary hospital for respiratory illnesses in Mexico City who had laboratory-confirmed S-OIV infection, also known as swine flu.

Methods We used retrospective medical chart reviews to collect data on the hospitalized patients. S-OIV infection was confirmed in specimens with the use of a real-time reverse-transcriptase–polymerase-chain-reaction assay.

Results From March 24 through April 24, 2009, a total of 18 cases of pneumonia and confirmed S-OIV infection were identified among 98 patients hospitalized for acute respiratory illness at the National Institute of Respiratory Diseases in Mexico City. More than half of the 18 case patients were between 13 and 47 years of age, and only 8 had preexisting medical conditions. For 16 of the 18 patients, this was the first hospitalization for their illness; the other 2 patients were referred from other hospitals. All patients had fever, cough, dyspnea or respiratory distress, increased serum lactate dehydrogenase levels, and bilateral patchy pneumonia. Other common findings were an increased creatine kinase level (in 62% of patients) and lymphopenia (in 61%). Twelve patients required mechanical ventilation, and seven died. Within 7 days after contact with the initial case patients, a mild or moderate influenza-like illness developed in 22 health care workers; they were treated with oseltamivir, and none were hospitalized.

Conclusions S-OIV infection can cause severe illness, the acute respiratory distress syndrome, and death in previously healthy persons who are young to middle-aged. None of the secondary infections among health care workers were severe.

Vaccine
Volume 27, Issue 40, Pages 5429-5542 (4 September 2009)
http://www.sciencedirect.com/science/journal/0264410X

Vaccination of children in low-resource countries against Shigella is unlikely to present an undue risk of reactive arthritis
Pages 5432-5434
J. S. Hill Gaston, Robert D. Inman, Edward T. Ryan, Malabi M. Venkatesan, Eileen M. Barry, Thomas L. Hale, A. Louis Bourgeois, Richard I. Walker

Abstract
Shigellosis is a major cause of morbidity and mortality among children in low-resource countries. Promising vaccine strategies in development include genetically attenuated Shigella, killed whole cell vaccines, subcellular vaccines, and O-polysaccharide–protein conjugates. There is a concern that Shigella vaccines could either induce reactive arthritis or could prime vaccinees for arthritis after a subsequent exposure to the pathogen because shigellosis is associated with reactive arthritis, especially in patients expressing the HLA B27 histocompatibility antigen. Our understanding of the pathogenesis of reactive arthritis is incomplete, and even surrogate biomarkers of bacterial arthritogenic activity have not yet been identified. Nonetheless, all of the Shigella vaccine strategies currently in development are designed to limit inflammation and intracellular antigen persistence that could trigger arthritogenic sequelae. The relatively low occurrence of the HLA B27 phenotype in most Shigella endemic areas, and the rarity of reported reactive arthritis in these populations, suggests that vaccination with attenuated, killed, or subcellular vaccines may not increase the background incidence of arthritic sequelae. More importantly, incidence rates of shigellosis in children living in low-resource countries suggest that, during maturation, the entire pediatric population may be infected with Shigella—possibly with devastating consequences. Therefore, clinical trials of candidate Shigella vaccines should be pursued aggressively in the developing world, beginning with a Phase 1 in HLA B27-negative volunteers, but proceeding to Phase 2 and Phase 3 in unscreened volunteers. Post-vaccination monitoring for possible reactive arthritis should be included in all clinical protocols.

Vaccine
Volume 27, Issue 40, Pages 5429-5542 (4 September 2009)
http://www.sciencedirect.com/science/journal/0264410X

Cost-effectiveness analysis of a cervical cancer vaccine in five Latin American countries
Pages 5519-5529
Lisandro Colantonio, Jorge A. Gómez, Nadia Demarteau, Baudouin Standaert, Andrés Pichón-Rivière, Federico Augustovski

Abstract
Implementation of cervical cancer (CC) vaccination in Latin America is expected to reduce the high CC burden in those countries. But the efficiency of such vaccination programs in the region still remains unknown. This study assesses the cost-effectiveness and cost-utility of introducing vaccination into the current CC disease management of five Latin American countries (Argentina, Brazil, Chile, Mexico, and Peru). The modelling results indicate that universal mass vaccination is cost-effective in the current health care setting of each country (<3× gross domestic product per capita, per country) with a substantial number of CC cases and deaths avoided in addition to an increase of quality-adjusted life years. This study will help guide the design of future clinical programmes and health-related policies. It will assist early and effective decision-making processes related to vaccine implementation in Latin America.

Vaccine
Volume 27, Issue 40, Pages 5429-5542 (4 September 2009)
http://www.sciencedirect.com/science/journal/0264410X

Attitudes towards influenza vaccination of multi-nationality health-care workers in Saudi Arabia
Pages 5538-5541
Jaffar A. Al-Tawfiq, Amalraj Antony, Mahmoud S. Abed

Abstract
Background
The compliance with influenza vaccination among health-care workers (HCWs) is known to be low. A multi-nationality survey to explore the reasons for such poor compliance has not been studied in depth.

Materials and methods
An epidemiologic survey to evaluate the compliance rates with influenza vaccination and possible associated reasons for compliance.

Results
A total of 450 survey sheets were distributed and 244 (54.2%) were completed. Of the total respondents, 51 (20.9%) were Saudi, 114 (46.7%) were other Arabs, 21 (4%) were North American, 21 (8.6%) were from UK or South Africa and 48 (19.7%) did not indicate their nationalities. There were 32 (13.1%) physicians, and 132 (54.1%) nurses. The overall influenza vaccination rate was 41% in the preceding year and 69% in the preceding 5 years, and 49.2% (n = 110) of the latter group received one to three vaccines. Of the total respondents, 156 (63.9%) report that the influenza vaccine was important, 86 (35%) report that they were not at risk of influenza, 163 (66.8%) report that the influenza vaccine was not safe and 152 (62.3%) report that influenza was not a serious illness. In a multivariate analysis, the following factors were important in choosing vaccinations: being a male, other Arab nationality, and knowing that influenza vaccine is important (P ≤ 0.01). Feeling at risk of influenza, and not using any vaccine alternatives, and that the vaccine is important for self and the patient’s protection, were statistically important factors as well (P ≤ 0.05).

Conclusion
Important factors associated with increasing influenza vaccine acceptance include being a male, other Arab nationality, and knowing that influenza vaccine is important. In addition, feeling at risk of influenza, and not using any vaccine alternatives, and that the vaccine is important for self and the patient’s protection, were statistically important factors as well. Thus, efforts to increase the acceptance rates should take these factors in consideration.

The WHO issued the fifth in its series of “briefing notes” on A/(H1N1) after ending its regular updates of confirmed cases and deaths with #58 issued 6 July 2009.

Pandemic (H1N1) 2009 briefing note 5

31 JULY 2009 | GENEVA — Research conducted in the USA and published 29 July in The Lancet [1] has drawn attention to an increased risk of severe or fatal illness in pregnant women when infected with the H1N1 pandemic virus.

Several other countries experiencing widespread transmission of the pandemic virus have similarly reported an increased risk in pregnant women, particularly during the second and third trimesters of pregnancy. An increased risk of fetal death or spontaneous abortions in infected women has also been reported.

Increased risk for pregnant women

Evidence from previous pandemics further supports the conclusion that pregnant women are at heightened risk.

While pregnant women are also at increased risk during epidemics of seasonal influenza, the risk takes on added importance in the current pandemic, which continues to affect a younger age group than that seen during seasonal epidemics.

WHO strongly recommends that, in areas where infection with the H1N1 virus is widespread, pregnant women, and the clinicians treating them, be alert to symptoms of influenza-like illness.

WHO recommendations for treatment

Treatment with the antiviral drug oseltamivir should be administered as soon as possible after symptom onset. As the benefits of oseltamivir are greatest when administered within 48 hours after symptom onset, clinicians should initiate treatment immediately and not wait for the results of laboratory tests.

While treatment within 48 hours of symptom onset brings the greatest benefits, later initiation of treatment may also be beneficial. Clinical benefits associated with oseltamivir treatment include a reduced risk of pneumonia (one of the most frequently reported causes of death in infected people) and a reduced need for hospitalization.

WHO has further recommended that, when pandemic vaccines become available, health authorities should consider making pregnant women a priority group for immunization.

Danger signs in all patients

Worldwide, the majority of patients infected with the pandemic virus continue to experience mild symptoms and recover fully within a week, even in the absence of any medical treatment. Monitoring of viruses from multiple outbreaks has detected no evidence of change in the ability of the virus to spread or to cause severe illness.

In addition to the enhanced risk documented in pregnant women, groups at increased risk of severe or fatal illness include people with underlying medical conditions, most notably chronic lung disease (including asthma), cardiovascular disease, diabetes, and immunosuppression. Some preliminary studies suggest that obesity, and especially extreme obesity, may be a risk factor for more severe disease.

Within this largely reassuring picture, a small number of otherwise healthy people, usually under the age of 50 years, experience very rapid progression to severe and often fatal illness, characterized by severe pneumonia that destroys the lung tissue, and the failure of multiple organs. No factors that can predict this pattern of severe disease have yet been identified, though studies are under way.

Clinicians, patients, and those providing home-based care need to be alert to danger signs that can signal progression to more severe disease. As progression can be very rapid, medical attention should be sought when any of the following danger signs appear in a person with confirmed or suspected H1N1 infection:

– shortness of breath, either during physical activity or while resting

– difficulty in breathing

– turning blue

– bloody or coloured sputum

– chest pain

– altered mental status

– high fever that persists beyond 3 days

– low blood pressure.

In children, danger signs include fast or difficult breathing, lack of alertness, difficulty in waking up, and little or no desire to play.

[1] Jamiesan DG et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009; published online July 29, 2009

http://www.who.int/csr/disease/swineflu/notes/h1n1_pregnancy_20090731/en/index.html

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) made recommendations for use of vaccine against novel influenza A (H1N1). The committee met to develop recommendations on who should receive vaccine against novel influenza A (H1N1) when it becomes available, and to determine which groups of the population should be prioritized if the vaccine is initially available in extremely limited quantities.

The ACIP recommended the vaccination efforts focus on five key populations.  The key populations “include those who are at higher risk of disease or complications, those who are likely to come in contact with novel H1N1, and those who could infect young infants.” When vaccine is first available, the committee recommended that programs and providers try to vaccinate:

– pregnant women,

– people who live with or care for children younger than 6 months of age,

– health care and emergency services personnel,

– persons between the ages of 6 months through 24 years of age, and

– people from ages 25 through 64 years who are at higher risk for novel H1N1 because of chronic health disorders or compromised immune systems.

The groups listed above total approximately 159 million people in the United States.

While the ACIP said it does not expect that there will be a shortage of novel H1N1 vaccine, it noted that “availability and demand can be unpredictable,” and that there is some possibility that initially the vaccine will be available in limited quantities. In this setting, the committee recommended that the following groups receive the vaccine before others:

– pregnant women,

– people who live with or care for children younger than 6 months of age,

– health care and emergency services personnel with direct patient contact,

– children 6 months through 4 years of age, and

– children 5 through 18 years of age who have chronic medical conditions.

The committee recognized the need to assess supply and demand issues at the local level. The committee further recommended that once the demand for vaccine for these prioritized groups has been met at the local level, programs and providers should begin vaccinating everyone from ages 25 through 64 years. Current studies indicate the risk for infection among persons age 65 or older is less than the risk for younger age groups. Therefore, as vaccine supply and demand for vaccine among younger age groups is being met, programs and providers should offer vaccination to people over the age of 65.

The committee also stressed that people over the age of 65 receive the seasonal vaccine as soon as it is available. Even if novel H1N1 vaccine is initially only available in limited quantities, supply and availability will continue, so the committee stressed that programs and providers continue to vaccinate unimmunized patients and not keep vaccine in reserve for later administration of the second dose.

The novel H1N1 vaccine “is not intended to replace the seasonal flu vaccine. It is intended to be used alongside seasonal flu vaccine to protect people. Seasonal flu and novel H1N1 vaccines may be administered on the same day.”

http://www.cdc.gov/media/pressrel/2009/r090729b.htm

CIDRAP News reports that the CDC will seek public input on plans for an A/H1N1 influenza vaccination drive later this year. CDC will hold ten “public engagement” meetings around the country to get citizen advice “on whether the vaccination program should be an all-out effort or something more modest,” according to Roger Bernier, PhD, MPH, senior advisor in the CDC’s National Center for Immunization and Respiratory Diseases. The CDC has scheduled a meeting in one city in each of the 10 Department of Health and Human Services (HHS) regions. Dates and locations for the all-day meetings include:

8 August: Denver, Colorado and Lincoln, Nebraska

15 August: Birmingham, Alabama, Sacramento, California and Vincennes, Indiana

22 August: El Paso, Texas, Bucks County (near Philadelphia), Pennsylvania, and New York City

29 August: Somerville, Massachusetts and Spokane, Washington.

http://www.cidrap.umn.edu/cidrap/content/influenza/swineflu/news/jul3109public.html

PATH said its scientists and collaborators “have developed formulation methods that protect hepatitis B vaccine from heat and freeze damage, helping to ensure the potency of hepatitis B vaccine in areas of the world where the cold chain is insufficient.” PATH said it published its findings in this month’s issue of Human Vaccines (volume 5, issue 8) in partnership with Arecor and the University of Colorado Denver School of Pharmacy. The article describes a new hepatitis B vaccine formulation exhibiting nine week stability at 55°C and at least six month stability at both 37°C and 45°C. The data indicate that the new hepatitis B vaccine formulation “will be better able to withstand disruption in the cold chain and could potentially be stored at room temperature for a significant part of its shelf life.” Additionally, PATH said its scientists and partners combined the heat-stable hepatitis B vaccine formulation with the freeze-protection technology developed earlier this year. The development of these formulation methods and the research described in both published studies were conducted in conjunction with PATH’s broad project work in vaccine stabilization, funded by the Bill & Melinda Gates Foundation.

http://www.path.org/news/pr090803-hepb.php

The Weekly Epidemiological Record (WER) for 31 July 2009, vol. 84, 31 (pp 309–324) includes: Cholera: global surveillance summary, 2008; WHO cholera information sources on the web.

http://www.who.int/wer/2009/wer8429.pdf

The Lancet
Aug 01, 2009   Volume 374  Number 9687   Pages 357 – 426
http://www.thelancet.com/journals/lancet/issue/current

Editorial
Supply and safety issues surrounding an H1N1 vaccine

The Lancet

Last week, Australia and the USA announced that they would begin trials of an H1N1 vaccine. Vaccination against H1N1 will be an important development in controlling the impact of the pandemic. However, several thorny issues exist around vaccine manufacture and approval.

All countries will require the vaccine but current global manufacturing capacity will not be able to meet this demand. Additionally, experts think that individuals might need two doses of the vaccine instead of one, reducing capacity further. Vaccine manufacturers are also struggling to produce good vaccine yields with the H1N1 seed virus.

One way to ease these supply problems is the use of adjuvants in a vaccine. On July 7, WHO’s Strategic Advisory Group of Experts on Immunization recommended that vaccine formulated with oil-in-water adjuvants and live-attenuated influenza vaccines should be promoted to help increase the global supply of a vaccine and because they are better at protecting against strain variations. Yet there are signs that the USA might not follow this recommendation. “Adjuvant use would be contingent upon showing that it was needed or clearly beneficial”, Jesse Goodman, acting chief scientist and deputy commissioner of the Food and Drug Administration told a press briefing on July 17. The USA must support the use of dose-sparing strategies to avoid depletion of an already short vaccine supply.

As well as availability, safety of an H1N1 vaccine is a concern. Many national regulatory agencies have set-up fast-track approval processes for the H1N1 vaccine, which means that a vaccine might be licensed without the usual safety and efficacy data requirements. Vaccine safety will therefore have to be monitored through post-marketing surveillance. But some fear a repeat of the 1976 H1N1 outbreak in the USA, where mass vaccination was associated with complications, which stopped the campaign and led to the withdrawal of the vaccine.

Countries need to assess carefully the risks and benefits of rapid approval of an H1N1 vaccine, especially since the disease has so far been mild with most patients making a full recovery. They must also ensure that they have strong post-marketing surveillance in place before rolling out a vaccine.

New England Journal of Medicine
Volume 361 — July 30, 2009 — Number 5
http://content.nejm.org/current.shtml

Original Article
Protection against a Malaria Challenge by Sporozoite Inoculation
M. Roestenberg and Others

ABSTRACT
Background An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites.

Methods We exposed 15 healthy volunteers — with 10 assigned to a vaccine group and 5 assigned to a control group — to bites of mosquitoes once a month for 3 months while they were receiving a prophylactic regimen of chloroquine. The vaccine group was exposed to mosquitoes that were infected with Plasmodium falciparum, and the control group was exposed to mosquitoes that were not infected with the malaria parasite. One month after the discontinuation of chloroquine, protection was assessed by homologous challenge with five mosquitoes infected with P. falciparum. We assessed humoral and cellular responses before vaccination and before the challenge to investigate correlates of protection.

Results  All 10 subjects in the vaccine group were protected against a malaria challenge with the infected mosquitoes. In contrast, patent parasitemia (i.e., parasites found in the blood on microscopical examination) developed in all five control subjects. Adverse events were mainly reported by vaccinees after the first immunization and by control subjects after the challenge; no serious adverse events occurred. In this model, we identified the induction of parasite-specific pluripotent effector memory T cells producing interferon-, tumor necrosis factor , and interleukin-2 as a promising immunologic marker of protection.

Conclusions   Protection against a homologous malaria challenge can be induced by the inoculation of intact sporozoites. (ClinicalTrials.gov number, NCT00442377 [ClinicalTrials.gov] .)

New England Journal of Medicine
Volume 361 — July 30, 2009 — Number 5
http://content.nejm.org/current.shtml

Editorial
Malaria Control — Addressing Challenges to Ambitious Goals
C. C. Campbell

Over the past 5 years, we have witnessed remarkable progress in malaria control. In Africa, the approach has been to “scale up for impact”1 by rapidly deploying insecticide-treated nets and providing artemisinin-based combination therapy. Programs in Equatorial Guinea, Ethiopia, Rwanda, Zambia, and Zanzibar have shown that when coverage of these interventions exceeds 50 to 60% of the population, the prevalence of infection with malaria parasites and mortality among children from such infection falls by 20 to 25% within 12 to 36 months.2

Progress has been based on highly effective and affordable malaria-control tools and mobilization of substantial funding at the global and national levels. Through the Global Fund to Fight AIDS, Tuberculosis and Malaria, almost $7 billion has been allocated for malaria programs since 2000.

Demonstration of the health effects that can be achieved with current control tools has sparked ambitions. Eradication of malaria is now the global goal. This has prompted comprehensive strategic planning, including the Global Malaria Action Plan3 and the Malaria Eradication Research Agenda,4 to prioritize investments in research and development.

History teaches that malaria-control interventions have inherent life expectancies. Resistance, notably that of Plasmodium falciparum, evolves as the intensity of drug use increases. The studies reported on in this issue of the Journal by Dondorp et al.5 (ClinicalTrials.gov number, NCT00493363 [ClinicalTrials.gov] , and Current Controlled Trials number, ISRCTN64835265 [controlled-trials.com] ) and Noedl et al.6 add to our understanding of the clinical and laboratory characterization and geographic distribution of artemisinin-resistant P. falciparum in Southeast Asia.

The artemisinin compounds are unique in the rapidity with which they kill malaria parasites. To minimize the development of resistance, artemisinins are combined with a second drug with a distinct mode of killing the malaria parasite. This artemisinin-based combination therapy has become the standard of treatment for malaria.

Resistance to malaria drugs has consistently emerged in Asia, specifically in western Cambodia, and spread to all areas with P. falciparum, except Central America and Hispaniola. Recent reports have sounded the alarm regarding a problem with the sensitivity of malaria parasites to artemisinin-based combination therapy. Dondorp et al. document a significant delay in parasitologic clearance in patients in western Cambodia.

They found that the delayed clearance derives from an impaired response to the artesunate component, not to the partner compound, mefloquine.

Using in vitro methods to characterize falciparum parasites from Bangladesh to the Thailand–Cambodia border, Noedl et al. demonstrate a significantly increased 50% inhibitory concentration of dihydroartemisinin required for parasites at sites on the Thailand–Cambodia border.

There is no question that this is resistance to artemisinin; history warns that it will intensify and spread unless containment steps are taken. Has the approach of combination therapy failed to protect the efficacy of artemisinin? Not necessarily. The most likely culprit is the widespread use of artemisinin as monotherapy in this region. To contain artemisinin resistance will require an understanding of human movement, limitation of the use of unregulated drug formulations and doses, and a rethinking of ineffective malaria-transmission control policies.

An intensive campaign coordinated by the World Health Organization has been launched to contain artemisinin resistance. The containment plan involves the rapid deployment of an efficacious artemisinin drug paired with an intensive effort to detect and rapidly treat all malaria infections. Deployment of insecticide-treated nets to decrease malaria transmission and screening and the treatment of migrants will be intensified, and more-thorough mapping of the geographic boundaries of the resistant parasites will be ramped up.

Modeling conducted by Maude et al.7 suggests that malaria transmission must be eliminated to snuff out the last resistant parasites. Is such elimination possible, or is the geographic expansion of artemisinin resistance inevitable? Slowing the spread of resistance will buy valuable time and save lives in the process. There is no alternative class of malaria drugs ready to replace the artemisinin derivatives.

The article in this issue by Roestenberg et al.8 (ClinicalTrials.gov number, NCT00442377 [ClinicalTrials.gov] ) adds evidence that the multidecade effort to develop malaria vaccines is on a positive trajectory. Their report reminds us that the whole malaria parasite is the most potent immunizing antigen identified to date.

Roestenberg et al. report on the immunization of human volunteers by means of repeated exposure to live P. falciparum sporozoites through bites of sporozoite-infected Anopheles stephensi mosquitoes. On subsequent challenge with mosquitoes infected with the same parasite strain, parasitemia developed in none of the 10 immunized volunteers but did develop in all 5 nonimmunized volunteers. Although the mosquito-inoculation approach used cannot be the basis for a human malaria vaccine, there has been considerable progress in the development of attenuated sporozoites that are sterile and standardized; products of these efforts are now entering clinical trials.9

Collins and Jeffery10 demonstrated that the inoculation of humans by P. falciparum sporozoites induces protection against the subsequent challenge of sporozoites with the same parasite strain. Over a 30-year period, radiation-attenuated sporozoites have been shown to be a potent immunogen, protecting more than 90% of subjects against infection.11

Currently, two approaches to the development of a malaria vaccine — the uses of whole parasites and subunit constructs — show promise. A recent study in the Journal by Abdulla et al.12 tested the RTS,S/AS02D candidate vaccine, which contains a subunit antigen targeting the hepatocyte stage of parasite development. The authors demonstrated an efficacy against first infection with P. falciparum malaria of approximately 65%. RTS,S is currently in phase 3 trials in several sites in Africa.

Malaria vaccines are moving from the laboratory into the real world. The vaccines that make it through testing and licensing will be deployed as part of malaria-control programs that distribute insecticide-treated bed nets and as an adjunct to control measures. Vaccines that can prevent, not just delay, the onset of infection would be a major plus in the endgame with falciparum transmission.

We are learning which approaches and time frames will be required to finish off malaria in the most challenging regions. The certainty is that new drugs active against artemisinin-resistant P. falciparum will be needed, possibly soon. Investment in a multipronged approach to vaccine development is imperative. Technical impediments to progress can be resolved.

The coming 5 years will be decisive. Will there be a sustained commitment to deploying lifesaving interventions to reach a majority of persons at risk for malaria? Will national leaders and global financing agencies balance near-term success with longer-term programs and ensure that investment in research and development of new technologies remains a priority? The answer must be yes. The question is how. Millions of African children await the answer.

No potential conflict of interest relevant to this article was reported.

Source Information

From the Malaria Control Program, Program for Appropriate Technology in Health (PATH), Seattle.

References

Steketee RW, Sipilanyambe N, Chimumbwa J, et al. National malaria control and scaling up for impact: the Zambia experience through 2006. Am J Trop Med Hyg 2008;79:45-52. [Free Full Text]

Bhattarai A, Ali AS, Kachur SP, et al. Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar. PLoS Med 2007;4:e309-e309. [CrossRef][Medline]

Global Malaria Action Plan for a malaria-free world. Geneva: Roll Back Malaria Partnership, 2009. (Accessed July 10, 2009, at http://rbm.who.int/gmap/index.html.)

Malaria Eradication Research Agenda (malERA) home page. (Accessed July 10, 2009, at http://malera.tropika.net/.)

Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009;361:455-467. [Free Full Text]

Noedl H, Socheat D, Satimai W. Artemisinin-resistant malaria in Asia. N Engl J Med 2009;361:540-541. [Free Full Text]

Maude RJ, Pontavornpinyo W, Saralamba S, et al. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J 2009;8:31-31. [CrossRef][Medline]

Roestenberg M, McCall M, Hopman J, et al. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 2009;361:468-477. [Free Full Text]

Luke TC, Hoffman SL. Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine. J Exp Biol 2003;206:3803-3808. [Free Full Text]

Collins WE, Jeffery GM. A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum: development of parasitologic and clinical immunity following secondary infection. Am J Trop Med Hyg 1999;61:Suppl:20-35. [Abstract]

Hoffman SL, Goh LM, Luke TC, et al. Protection of humans against malaria by immunization with radiation attenuated Plasmodium falciparum sporozoites. J Infect Dis 2002;185:1155-1164. [CrossRef][Web of Science][Medline]

Abdulla S, Oberholzer R, Juma O, et al. Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med 2008;359:2533-2544. [Free Full Text]

PLoS Medicine
(Accessed 3 August 2009)
http://medicine.plosjournals.org/perlserv/?request=browse&issn=1549-1676&method=pubdate&search_fulltext=1&order=online_date&row_start=1&limit=10&document_count=1533&ct=1&SESSID=aac96924d41874935d8e1c2a2501181c#results

Editorial
Ethics Without Borders.

The PLoS Medicine Editors (2009)

Many nongovernmental organizations (NGOs) provide medical care and humanitarian assistance to some of the most vulnerable populations on earth. Increasingly, such organizations are also important producers of health research, which can range from simple health surveys or interview studies, to complex clinical trials.

There is little doubt that the results of such research can be immensely valuable. First, they may be critical in informing the scale and type of interventions an NGO may need to deliver—for example, a survey of growth among children being treated for malnutrition [1]. Second, they may provide crucial data against which the effects of ongoing events can be monitored—for example, the effect on displaced populations of access to maternal health care [2]. Third, they may be used to inform health policy at the highest levels—for example, studies of anti-malarial efficacy among populations served by NGOs can inform recommendations for treatment regimens internationally (reviewed in [3]).

Data collection at NGOs, however, does not have research per se as its primary aim. Rather, it is usually, and rightly, aimed at improvement of delivery of care to populations who normally lack access to services; it often also provides evidence for advocacy on behalf of these populations. Undoubtedly the tension between research and delivery of care is not easy for NGOs to reconcile, catapulting as it does what are essentially care-providing organizations into a whole different sphere—that of scientific investigation involving human participants. Such endeavors raise new and important issues of oversight. Not least, the procedures necessary for ethical conduct of research [4], above and beyond accepted health care guidelines, may not always fit naturally into the established operations of NGOs. Nonetheless, international ethical standards require adequate oversight whenever a line is crossed from simple delivery of care to asking a research question. Knowing where the line lies is one of the most difficult issues for researchers, organizations, and, increasingly, for journals.

Most would accept the need for the ethical review of randomized clinical trials, and that registration in a clinical trials registry plus proper reporting is best research practice [5]. But what about other types of research—such as the example above of a nutritional survey for the purposes of monitoring the growth of children or a human rights investigation of the health care experiences of drug abusers in detention [6]? We’d argue that if the research is done with the intention of gaining generalizable knowledge or publishable results, rather than performing a routine internal audit, it is by definition research and ethical oversight is needed.

This is not a new concept: the need for oversight in research comes out of the long history of the development of protection of research participants. Such guidelines include the Declaration of Helsinki and the International Ethical Guidelines for Biomedical Research Involving Human Subjects from the Council for International Organizations of Medical Sciences [7], which lay out the four basic principles underlying need for ethical review: respect for persons; beneficence; nonmaleficence; and justice. Interestingly, these guidelines note that “the subjects selected should be the least vulnerable necessary to accomplish the purposes of the research”—a clause that poses immediate issues for NGOs who necessarily work with the most vulnerable populations.

In an article this month in PLoS Medicine on the experiences of the Médecins Sans Frontières (MSF) research ethics review board [8], Doris Schopper and colleagues discuss how the board has attempted to define what constitutes research, develop a review process appropriate for the organization, and provide adequate protection for participants in research carried out by MSF. There is no question that the research done by MSF and other humanitarian organizations is done in the most difficult of circumstances—“research on the run” as one of the moderators at a recent United Kingdom MSF research event [9] called it—and that there are practical difficulties in obtaining and providing oversight for these organizations, which simply do not apply in other research contexts. What perhaps lies behind some of the hesitation in applying ethical guidelines to the research that NGOs do is a concern that this oversight may interfere with the practicalities of doing the research—that “there’s no time” to get ethical approval, or no time for an appropriate board to be set up. By setting up its own independent board, MSF has gone a long way to fill in for a lack of ethical boards in many of the places where they work. But as Schopper and colleagues describe, they have gone further by establishing procedures for obtaining “emergency” review and approval when time is short.

What should be the role of journals in this process? Journals and editors are primarily facilitators for the dissemination of research. However, they also have a duty to ensure that the research they publish adheres to accepted ethical standards. While journal editors cannot affect work already done, they can support initiatives such as the MSF research ethics board and can continue to require clear documentation, both upon submission and within the published article itself, that the research was conducted ethically and ethical review was sought. Ultimately, by refusing to consider for publication research papers that lack ethical review, journals can promulgate an expectation that organizations incorporate such review into their research plans. To lose important research evidence from NGOs due to lack of appropriate oversight constitutes a tremendous waste of the resources involved in conducting the research, introduces a potential source of bias in the literature, and ultimately betrays the trust of research participants.

NGOs have a long and proud history of caring and speaking for the most vulnerable populations. That such organizations now conduct research to inform their care and advocacy is to be welcomed. Their messages are widely heard; conducting and publishing high-quality research that adheres to the highest principles can only empower their voices further.

Lapidus N, Luquero FJ, Gaboulaud V, Shepherd S, Grais RF (2009) Prognostic accuracy of WHO growth standards to predict mortality in a large-scale nutritional program in Niger. PLoS Med 6: e1000039. doi:10.1371/journal.pmed.1000039.

Mullany LC, Lee CI, Yone L, Paw P, Oo EKS, et al. (2008) Access to essential maternal health interventions and human rights violations among vulnerable communities in eastern Burma. PLoS Med 5: e242. doi:10.1371/journal.pmed.0050242.

Guthmann J-P, Checchi F, van den Broek I, Balkan S, van Herp M, et al. (2008) Assessing antimalarial efficacy in a time of change to artemisinin-based combination therapies: The Role of Médecins Sans Frontières. PLoS Med 5: e169. doi:10.1371/journal.pmed.0050169.

World Medical Association (2008) Declaration of Helsinki: Ethical principles for medical research involving human subjects. Available: http://www.wma.net/e/policy/b3.htm. Accessed 29 June 2009.

Public Library of Science (2009) PLoS Medicine editorial and publishing policies. Clinical trials. Available: http://www.plosmedicine.org/static/polic​ies.action#clinical_trials . Accessed 29 June 2009.

Cohen JE, Amon JJ (2008) Health and human rights concerns of drug users in detention in Guangxi Province, China. PLoS Med 5: e234. doi:10.1371/journal.pmed.0050234.

Council for International Organizations of Medical Sciences (2002) International ethical guidelines for biomedical research involving human subjects. Available: http://www.cioms.ch/frame_guidelines_nov​_2002.htm . Accessed 29 June 2009.

Schopper D, Upshur R, Matthys F, Singh JA, Bandewar SS, et al. (2009) Research ethics review in humanitarian contexts: The experience of the independent ethics review board of Médecins Sans Frontières. PLoS Med 6: e1000115. doi:10.1371/journal.pmed.1000115.

Médecins Sans Frontières (2009) Scientific day 2009. Available: http://www.msf.org.uk/sciday09.event. Accessed 29 June 2009.

Vaccine
Volume 27, Issue 38, Pages 5171-5292 (20 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Short Communications
Vaccine production capacity for seasonal and pandemic (H1N1) 2009 influenza
Nicolas Collin, Xavier de Radiguès and the World Health Organization H1N1 Vaccine Task Force

Abstract
The first influenza pandemic of the 21st century, due to a new strain of A(H1N1) virus, was declared on 11 June 2009 by the Director-General of the World Health Organization. Fortunately, the international community, including influenza vaccine manufacturers, has been increasing its preparedness for such an event, triggered by the need to stem the spread of the highly pathogenic avian influenza A(H5N1) virus over recent years. Today, the development of a pandemic influenza vaccine in the fastest possible time is a global priority. However, two major issues need to be taken into consideration: how long will it take to produce sufficient pandemic vaccine doses to immunize the global population at risk, including poor populations that have no resources to purchase the vaccine; and how will pandemic vaccine production affect availability of trivalent vaccine for the forthcoming 2009–2010 influenza season. To address these questions, WHO carried out a survey in May 2009 among influenza vaccine manufacturers on their planned seasonal and pandemic production with a view to developing recommendations on the distribution and use of pandemic influenza vaccine.

Vaccine
Volume 27, Issue 38, Pages 5171-5292 (20 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Regular Papers
Attitudes toward HPV vaccination among parents of adolescent girls in Mysore, India
Pages 5203-5208
Purnima Madhivanan, Karl Krupp, M.N. Yashodha, Laura Marlow, Jeffrey D. Klausner, Arthur L. Reingold

Abstract
This study investigates attitudes toward human papillomavirus (HPV) vaccination among parents of adolescent girls in Mysore, India. Seven focus group discussions were held among parents of adolescent girls stratified by sex, religion and region to explore attitudes about cervical cancer and HPV vaccination. The study found that while parents have limited knowledge about HPV or cervical cancer, most are still highly accepting an HPV vaccine. In addition, high acceptability levels appear to reflect positive attitudes toward the government universal immunization program in general, rather than to the HPV vaccine in particular. The results highlight the need for additional education and health promotion regarding HPV and cervical cancer prevention in India.

The WHO issued the fourth in its series of “briefing notes” on A/(H1N1), after ending its regular updates of confirmed cases and deaths with #58 issued 6 July 2009.

Pandemic (H1N1) 2009 briefing note 4

Preliminary information important for understanding the evolving situation

24 JULY 2009 | GENEVA — The number of human cases of pandemic (H1N1) 2009 is still increasing substantially in many countries, even in countries that have already been affected for some time.

Our understanding of the disease continues to evolve as new countries become affected, as community-level spread extends in already affected countries, and as information is shared globally. Many countries with widespread community transmission have moved to testing only samples of ill persons and have shifted surveillance efforts to monitoring and reporting of trends. This shift has been recommended by WHO, because as the pandemic progresses, monitoring trends in disease activity can be done better by following trends in illness cases rather than trying to test all ill persons, which can severely stress national resources. It remains a top priority to determine which groups of people are at highest risk of serious disease so steps to best to protect them can be taken.

In addition to surveillance information, WHO is relying on the results of special research and clinical studies and other data provided by countries directly through frequent expert teleconferences on clinical, virological and epidemiological aspects of the pandemic, to gain a global overview of the evolving situation.

Average age of cases increasing

In most countries the majority of pandemic (H1N1) 2009 cases are still occurring in younger people, with the median age reported to be 12 to 17 years (based on data from Canada, Chile, Japan, UK and the United States of America). Some reports suggest that persons requiring hospitalization and patients with fatal illness may be slightly older.

As the disease expands broadly into communities, the average age of the cases is appearing to increase slightly. This may reflect the situation in many countries where the earliest cases often occurred as school outbreaks but later cases were occurring in the community. Some of the pandemic disease patterns differ from seasonal influenza, where fatal disease occurs most often in the elderly (>65 years old). However, the full picture of the pandemic’s epidemiology is not yet fully clear because in many countries, seasonal influenza viruses and pandemic (H1N1) 2009 viruses are both circulating and the pandemic remains relatively early in its development.

Although the risk factors for serious pandemic disease are not know definitively, risk factors such as existing cardiovascular disease, respiratory disease, diabetes and cancer currently are considered risk factors for serious pandemic (H1N1) 2009 disease. Asthma and other forms of respiratory disease have been consistently reported as underlying conditions associated with an augmented risk of severe pandemic disease in several countries.

A recent report suggests obesity may be another risk factor for severe disease. Similarly, there is accumulating evidence suggesting pregnant women are at higher risk for more severe disease. A few preliminary reports also suggest increased risk of severe disease may be elevated in some minority populations, but the potential contributions of cultural, economic and social risk factors are not clear.

Vaccine situation

The development of new candidate vaccine viruses by the WHO network is continuing to improve yields (currently 25% to 50 % of the normal yields for seasonal influenza for some manufacturers). WHO will be able to revise its estimate of pandemic vaccine supply once it has the new yield information. Other important information will also be provided by results of ongoing and soon-to be-initiated vaccine clinical trials. These trials will give a better idea of the number of doses required for a person to be immunized, as well as of the quantity on active principle (antigen) needed in each vaccine dose.

Manufacturers are expected to have vaccines for use around September. A number of companies are working on the pandemic vaccine production and have different timelines.

http://www.who.int/csr/disease/swineflu/notes/h1n1_situation_20090724/en/index.html

The Weekly Epidemiological Record (WER) for 24 July 2009, vol. 84, 30 (pp 301–308) includes: Strategic Advisory Group of Experts on Immunization – report of the extraordinary meeting on the influenza A (H1N1) 2009 pandemic, 7 July 2009; Human infection with pandemic A (H1N1) 2009 influenza virus: clinical observations in hospitalized patients, Americas, July 2009 – update

http://www.who.int/wer/2009/wer8429.pdf

The transcript of the CDC Briefing on Investigation of Human Cases of H1N1 Flu from 24 July 2009 was released. Dr. Anne Schuchat, Director of the National Center For Immunization and Respiratory Diseases, responded to media questions. The full transcript is available at the link below.  Selected comments are presented here:

“…I want to make a special reminder to health care workers.  We have recommended health care workers get the seasonal flu vaccine for years and we all need to be with vaccination coverage.  This year in particular we want to keep health care workers healthy at work able to care for sick patients, and we don’t want them to be spreading influenza to their patients.  We recommend them strongly to receive the seasonal flu vaccine. And I’m expecting when H1N1 vaccine recommendations come out it’s very, very likely health care workers will be in that group that ought to get vaccines as well…”

“…A second area that’s very active is the efforts around vaccines.  I think the media heard yesterday from the FDA and the NIH about efforts being carried out around clinical trials and vaccine development.  And I want to remind you that next Wednesday, July 29th, CDC’s Advisory Committee On Immunization Practices will be convening here in Atlanta.  They will be deliberating recommendations for which populations should be targeted for the H1N1 vaccine and whether prioritization is going to be appropriate.  We also provided planning scenarios to the state and local health departments so that they can be working carefully with the private sector, with the health systems, with communities and communicators about vaccination preparations.  At this point the secretary has announced that we are planning for a voluntary vaccination program in the fall, assuming availability of appropriate vaccines and that the virus hasn’t changed so substantially that a vaccine wouldn’t work.  So there’s a lot going on to be ready for such an effort.  And this ACIP committee meeting next week will be a key step in that process…”

“…So the second part of your question was about mandates.  Mandates for immunization for school entry are a state and local matter.  The immunized states, every state mandates use of certain vaccines for school entry, such as measles vaccine.  Influenza hasn’t typically been a vaccine that has been on that same kind of listing.  Measles, of course, is a disease that we have eliminated in The United States.  Much of the tremendous control that we’ve had with measles has been through high immunization coverage, as well as high second dose coverage, which is where the school entry requirements came through.  So at this point I am not anticipating mandated influenza vaccine for school-aged children.  But whatever happens, that will be a state and local matter…”

http://www.cdc.gov/media/transcripts/2009/t090724.htm

The National Institute of Allergy and Infectious Diseases (NIAID) said it is set to begin a series of clinical trials to gather critical data about influenza vaccines, including two candidate H1N1 flu vaccines. NIAID Director Anthony S. Fauci, M.D. said, “With the emergence of the 2009 H1N1 influenza virus, we have undertaken a collaborative and efficient process of vaccine development that is proceeding in stepwise fashion…Now, NIAID will use our longstanding vaccine clinical trials infrastructure — the Vaccine and Treatment Evaluation Units — to help quickly evaluate these pilot lots (of vaccine) to determine whether the vaccines are safe and to assess their ability to induce protective immune responses. These data will be factored into the decision about how and if to implement a 2009 H1N1 flu immunization program this fall.”

NIAID said that initial studies will look at whether one or two 15 microgram doses of H1N1 vaccine are needed to induce a potentially protective immune response in healthy adult volunteers (aged 18 to 64 years old) and elderly people (aged 65 and older). Researchers also will assess whether one or two 30 microgram doses are needed. The doses will be given 21 days apart, testing two manufacturers’ vaccines (Sanofi Pasteur and CSL Biotherapies). If early information from those trials indicates that these vaccines are safe, similar trials in healthy children (aged 6 months to 17 years old) will begin.

The agency noted that a concurrent set of trials will look at the safety and immune response in healthy adult and elderly volunteers who are given the seasonal flu vaccine along with a 15 microgram dose of 2009 H1N1 vaccine. The H1N1 vaccine would be given to different sets of volunteers either before, after, or at the same time as the seasonal flu vaccine. If early information from those studies indicates that these vaccines are safe, similar trials in healthy children (aged 6 months to 17 years old) will start.

Finally, NIOAID said, a panel of outside experts will conduct a close review of the safety data from these trials to spot any safety concerns in real time. Information from these studies in healthy people will help public health officials develop recommendations for immunization schedules, including the optimal dosage and number of doses for multiple age and groups, including adults, the elderly, and children. Data may also be used to support decisions about the best recommendations for people in high risk groups, including pregnant women and people whose immune systems are weakened or otherwise compromised.

The trials “are being conducted in a compressed timeframe in a race against the possible autumn resurgence of 2009 H1N1 flu infections that may occur at the same time as seasonal influenza virus strains begin to circulate widely in the Northern Hemisphere.”

NIAID noted that its Vaccine and Treatment Evaluation Units (VTEUs) network consists of eight university research hospitals and medical organizations across the United States that “provide a ready resource for conducting clinical trials that evaluate vaccines and treatments for a wide array of infectious diseases,” and that the network’s rapid-response capability is “especially important for testing vaccines designed to counteract emerging public health concerns. Results are expected to be available weeks after the trials begin.”

NIAID’s Vaccine and Treatment Evaluation Units include the following:

– Baylor College of Medicine, Houston

– Children’s Hospital Medical Center, Cincinnati

– Emory University, Atlanta

– Group Health Cooperative, Seattle

– Saint Louis University, St. Louis

– University of Iowa, Iowa City

– University of Maryland School of Medicine, Baltimore

– Vanderbilt University, Nashville, Tenn

http://www.nih.gov/news/health/jul2009/niaid-22.htm

The MMWR July 24, 2009 / 58 (Early Release);1-52 includes: Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009

Prepared by Anthony E. Fiore, MD1; David K. Shay, MD1; Karen Broder, MD2; John K. Iskander, MD2; Timothy M. Uyeki, MD1; Gina Mootrey, DO3; Joseph S. Bresee, MD1
Nancy J. Cox, PhD1

1Influenza Division, National Center for Immunization and Respiratory Diseases
2Immunization Safety Office, Division of Healthcare Quality Promotion, National Center for Preparedness, Detection and Control of Infectious Diseases
3Immunization Services Division, National Center for Immunization and Respiratory Diseases
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr58e0724a1.htm