The WHO continues to issue weekly “updates” and briefing notes as below:
Pandemic (H1N1) 2009 – update 71
Weekly update

As of 17 October 2009, worldwide there have been more than 414,000 laboratory confirmed cases of pandemic influenza H1N1 2009 and nearly 5000 deaths reported to WHO.

As many countries have stopped counting individual cases, particularly of milder illness, the case count is significantly lower than the actually number of cases that have occurred. WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and member states and through monitoring of multiple sources of data.
New Activity:
Mongolia, Rwanda, and Sao Tome and Principe have reported pandemic influenza cases for the first time this week.
Iceland, Sudan, and Trinidad and Tobago reported their first fatal cases.
Situation update:
In general, influenza activity in the northern hemisphere is much the same as in the last week, though respiratory disease activity continues to spread and increase in intensity. In North America, the U.S.A. is still reporting nationwide rates of Influenza-Like Illness (ILI) well above baseline rates with high rates of pandemic H1N1 2009 virus detections in clinical laboratory specimens (29% of all specimens tested are positive for influenza A and all of those subtyped are pandemic H1N1 2009 virus. Canada reports increases in ILI rates for the fourth straight week but the highest level of activity is in the western province of British Columbia. Mexico still reports active transmission in some areas of the country. Although influenza activity is low in most countries in Europe, in Belgium, Israel, the Netherlands, Norway, and parts of the United Kingdom consultation ILI/ARI rates are above baseline levels. Similarly the number of influenza virus detections relatively high, which may indicate the early start of an influenza season. Rates of respiratory illness in Eastern Europe and Northern Asia are increasing but are not yet at levels normally seen in an influenza season (baseline levels are not defined in many countries of the area). Of note, the proportion of cases in Asia that are related to seasonal influenza A(H3N2) continue to decline globally as the proportion related to pandemic H1N1 2009 virus increases. Currently, only East Asia is reporting any significant numbers of influenza A(H3N2) isolates.
In tropical areas of the world, rates of illness are generally declining, with a few exceptions. Cuba, Colombia, and El Salvador are reporting increases in the tropical region of the Americas. In tropical Asia, of the countries that are reporting this week, all report decreases in respiratory disease activity.
The temperate region of the southern hemisphere has no significant pandemic related activity in the past week.

Weekly update (Virological surveillance data)

http://www.who.int/csr/don/2009_10_23/en/index.html

New York Governor David A. Paterson announced that State Health Commissioner Richard F. Daines, M.D., “has suspended the mandatory influenza immunization requirement for New York health care workers so that the limited vaccine supplies can be used for populations most at risk of serious illness and death – especially pregnant women and children and young people between the ages of 6 months and 24 years.” Governor Paterson said, “Over the last week, the Centers for Disease Control and Prevention (CDC) acknowledged that New York would only receive approximately 23 percent of its anticipated vaccine supply by the end of the month. As a result, we need to be as resourceful as we can with the limited supplies of vaccine currently coming into the State and make sure that those who are at the highest risk for complications from the H1N1 flu receive the first vaccine being distributed right now in New York State.”
Commissioner Daines continued, “We had told hospitals that if they had to choose between vaccinating patients or employees to vaccinate patients first. This week, the CDC confirmed that most of the national supply of seasonal flu vaccine has been distributed, and that H1N1 vaccine distribution is far behind projections. New evidence is showing that H1N1 can be especially virulent to pregnant women and young people – so they should get vaccinated first.” http://www.ny.gov/governor/press/press_1022094.html

The World Health Organization (WHO), UNICEF and the World Bank jointly released “The State of the World’s Vaccines and Immunization, Third Edition” which reports that “more infants are being immunized today than ever before – a record 106 million in 2008,” but that “…life-saving vaccines, now common in wealthy countries, still do not reach an estimated 24 million children who are most at risk and at least an additional US$1 billion per year will be needed to ensure that new and existing vaccines will be delivered to all children in the 72 poorest countries.” Dr Margaret Chan, Director-General, WHO. Commented, “The influenza pandemic draws attention to the promise and dynamism of vaccine development today. Yet it reminds us once again of the obstacles to bringing the benefits of science to people in the poorest nations. We must overcome the divide that separates rich from poor – between those who get life-saving vaccines, and those who don’t.”

The report notes that at least 120 vaccines – a record number – are now available against deadly diseases. In addition, over 80 new products are in late-stage clinical testing, including more than 30 that target diseases for which no vaccine currently exists. At the same time, a significant number of vaccine candidates, including ones targeting diseases such as HIV/AIDS, malaria, tuberculosis and dengue, are moving through the research pipeline.

The report also notes that the global vaccine market has tripled over the last eight years, reaching more than US$17 billion in revenue, and that “rising demand for vaccines via United Nations procuring agencies and a renaissance in vaccine discovery and development have fueled industry’s renewed focus on vaccines.” Significantly, the report notes, “manufacturers in developing countries are now meeting 86 % of the global demand for traditional vaccines, such as those protecting against measles, whooping cough (pertussis), tetanus and diphtheria.”

Report available at: http://www.who.int/immunization/sowvi/en/index.html

http://www.who.int/mediacentre/news/releases/2009/state_immunizaton_20091021/en/index.html

The Bill & Melinda Gates Foundation today announced 76 grants of US$100,000 each “to pursue bold ideas for transforming health in developing countries” as part of its Grand Challenges Explorations program. The grants will support researchers in 16 countries.  Dr. Tachi Yamada, president of the Gates Foundation’s Global Health Program, said, “Some of the biggest stumbling blocks in global health are now being overcome with promising new vaccines and treatments. The Grand Challenges Explorations  will continue to fill the pipeline with possibilities and hopefully produce a breakthrough idea that could save untold numbers of lives.” Grantees from round 3 were selected from almost 3,000 proposals. Gates said “all levels of scientists are represented – from young post-graduate investigators to veteran researchers – as are a wide range of disciplines, such as chemistry, bioengineering, electronics, mechanical engineering, infectious disease, and epidemiology. They are based at universities, research institutes, nonprofit organizations, and private companies around the world.”

Grants involving vaccines and immunology included:

– Cecil Czerkinsky of the International Vaccine Institute in Korea will explore whether vaccines administered under the tongue can produce strong immune responses in distant organs such as the lungs and reproductive tract;

– Margaret Njoroge of Med Biotech Laboratories in Uganda will develop an intranasal vaccine for mothers, designed to induce antibodies against malaria in breast milk and confer immunity on their babies;

– Kate Edwards, at the University of San Diego will study how a brief bout of exercise may enhance the efficiency of pneumococcal vaccine.

Grand Challenges Explorations web site

http://www.gatesfoundation.org/press-releases/Pages/grand-challenges-explorations-round-three-winners-091020.aspx

The World Epidemiological Record (WER) for 23 October 2009, vol. 84, 43 (pp 445–452) includes: Progress towards eradicating poliomyelitis in Nigeria, January 2008–July 2009; Global Action Plan for the Prevention and Control of Pneumonia in children aged under 5 years
http://www.who.int/wer/2009/wer8443.pdf

The MMWR for 23 October 2009 / Vol. 58 / No. 41 includes:
– Introduction and Transmission of 2009 Pandemic Influenza A (H1N1) Virus — Kenya, June–July 2009
– Reduction in Rotavirus After Vaccine Introduction — United States, 2000–2009
– Progress Toward Poliomyelitis Eradication — Nigeria, January 2008–July 2009

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

The Lancet
Oct 24, 2009  Volume 374  Number 9699   Pages 1393 – 1472
http://www.thelancet.com/journals/lancet/issue/current

Editorial
Vaccines and the world of child health
The Lancet
Preview
For those in developed countries the few vaccinations of our early years are a distant memory. It is easy to take for granted not only the invisible and long-lasting protective veil that vaccinations draw against potentially fatal infectious diseases, but also the public health transformation wrought by vaccines and other interventions in the past century. Our enviable life expectancy and economic success both depend on them.

The Lancet Infectious Disease
Nov 2009  Volume 9  Number 11  Pages 651 – 718
http://www.thelancet.com/journals/laninf/issue/current

Leading Edge
HIV vaccine trials and tribulations
The Lancet Infectious Diseases

Preview
The results released on Sept 24 of the RV144 trial of a vaccine against HIV offer a glimmer of hope in a field that has experienced many disappointments. The reported vaccine efficacy of 31% for prevention of HIV infection seems promising, but still leaves the prospect of immunisation as a practical public health intervention against HIV tantalisingly out of reach.

The Lancet Infectious Disease
Nov 2009  Volume 9  Number 11  Pages 651 – 718
http://www.thelancet.com/journals/laninf/issue/current

Progress towards a dengue vaccine
Daniel P Webster, Jeremy Farrar, Sarah Rowland-Jones

The spread of dengue virus throughout the tropics represents a major, rapidly growing public health problem with an estimated 2.5 billion people at risk of dengue fever and the life-threatening disease, severe dengue. A safe and effective vaccine for dengue is urgently needed. The pathogenesis of severe dengue results from a complex interaction between the virus, the host, and, at least in part, immune-mediated mechanisms. Vaccine development has been slowed by fears that immunisation might predispose individuals to the severe form of dengue infection.

Vaccine
Volume 27, Issue 46, Pages 6393-6480 (30 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

Advances in Vaccine Technology II 2008: Introduction
Edited by David B. Weiner, Mathura P. Ramanathan, Barry C. Buckland, Kathrin U. Jansen and John G. Auninš

Emerging diseases, zoonoses and vaccines to control them
Pages 6435-6438
Pastoret Paul-Pierre
Abstract
Vaccination, when available, is undoubtedly the most cost-effective means of preventing and controlling, and even eradicating, infectious diseases. In recent years vaccination has also been used for other purposes in animal health, production and welfare, e.g. immunocastration.
Vaccination of animals serves many different purposes, such as controlling animal infections and infestations, thus improving animal health and welfare; controlling anthropozoonoses and food poisoning in humans, thereby protecting public health; solving problems associated with antibiotic and anthelmintic resistance; helping to leave food-producing animals free of chemical residues; protecting the environment and biodiversity and ensuring animal farming sustainability. The problem is nevertheless more complex when facing emerging or re-emerging infections particularly zoonotic ones.

Pandemic (H1N1) 2009 briefing note 13
Clinical features of severe cases of pandemic influenza

16 OCTOBER 2009 | GENEVA — To gather information about the clinical features and management of pandemic influenza, WHO hosted a three-day meeting at the headquarters of the Pan American Health Organization in Washington, DC on 14–16 October. Findings and experiences were presented by around 100 clinicians, scientists, and public health professionals from the Americas, Europe, Asia, Africa, the Middle East and Oceania.

The meeting confirmed that the overwhelming majority of persons worldwide infected with the new H1N1 virus continue to experience uncomplicated influenza-like illness, with full recovery within a week, even without medical treatment.

Need for intensive care

However, concern is now focused on the clinical course and management of small subsets of patients who rapidly develop very severe progressive pneumonia. In these patients, severe pneumonia is often associated with failure of other organs, or marked worsening of underlying asthma or chronic obstructive airway disease.

Treatment of these patients is difficult and demanding, strongly suggesting that emergency rooms and intensive care units will experience the heaviest burden of patient care during the pandemic.

Primary viral pneumonia is the most common finding in severe cases and a frequent cause of death. Secondary bacterial infections have been found in approximately 30% of fatal cases. Respiratory failure and refractory shock have been the most common causes of death.

Presentations during the meeting explored the pathology of severe disease in detail, with findings supported by work in experimental animals. These findings confirm the ability of the new H1N1 virus to directly cause severe pneumonia.

Clinical picture different from seasonal influenza

Participants who have managed such cases agreed that the clinical picture in severe cases is strikingly different from the disease pattern seen during epidemics of seasonal influenza. While people with certain underlying medical conditions, including pregnancy, are known to be at increased risk, many severe cases occur in previously healthy young people. In these patients, predisposing factors that increase the risk of severe illness are not presently understood, though research is under way.

In severe cases, patients generally begin to deteriorate around 3 to 5 days after symptom onset. Deterioration is rapid, with many patients progressing to respiratory failure within 24 hours, requiring immediate admission to an intensive care unit. Upon admission, most patients need immediate respiratory support with mechanical ventilation. However, some patients do not respond well to conventional ventilatory support, further complicating the treatment.

On the positive side, findings presented during the meeting add to a growing body of evidence that prompt treatment with the antiviral drugs, oseltamivir or zanamivir, reduces the severity of illness and improves the chances of survival. These findings strengthen previous WHO recommendations for early treatment with these drugs for patients who meet treatment criteria, even in the absence of a positive confirmatory test.

In addition to pneumonia directly caused by replication of the virus, evidence shows that pneumonia caused by co-infection with bacteria can also contribute to a severe, rapidly progressive illness. Bacteria frequently reported include Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant strains in some cases. As these bacterial co-infections are more frequent than initially recognized, clinicians stressed the need to consider empiric antimicrobial therapy for community acquired pneumonia as an early treatment.

Groups at greatest risk

Participants agreed that the risk of severe or fatal illness is highest in three groups: pregnant women, especially during the third trimester of pregnancy, children younger than 2 years of age, and people with chronic lung disease, including asthma. Neurological disorders can increase the risk of severe disease in children.

Evidence presented during the meeting further shows that disadvantaged populations, such as minority groups and indigenous populations, are disproportionately affected by severe disease. Although the reasons for this heightened risk are not yet fully understood, theories being explored include the greater frequency of co-morbidities, such as diabetes and asthma, often seen in these groups, and lack of access to care.

Although the exact role of obesity is poorly understood at present, obesity and especially morbid obesity have been present in a large portion of severe and fatal cases. Obesity has not been recognized as a risk factor in either past pandemics or seasonal influenza.

WHO and its partners are providing technical guidance and practical support to help developing countries better detect and treat illness caused by the pandemic virus. Patient care advice that can be applied in resource-limited settings is being rapidly compiled.

http://www.who.int/csr/disease/swineflu/notes/h1n1_clinical_features_20091016/en/index.html

The U.S. Food and Drug Administration approved use of Merck’s Gardasil vaccine for the prevention of genital warts (condyloma acuminata) due to HPV types 6 and 11 in boys and men, ages 9 through 26, noting that each year, about 2 out of every 1,000 men in the United States are newly diagnosed with genital warts. Karen Midthun, M.D., acting director of the FDA’s Center for Biologics Evaluation and Research, said, “This vaccine is the first preventive therapy against genital warts in boys and men ages 9 through 26, and, as a result, fewer men will need to undergo treatment for genital warts.” Gardasil’s effectiveness was studied in a randomized trial of 4,055 males ages 16 through 26 years old. The results showed that in men who were not infected by HPV types 6 and 11 at the start of the study, Gardasil was nearly 90 percent effective in preventing genital warts caused by infection with HPV types 6 and 11. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm187003.htm

Science
16 October 2009  Vol 326, Issue 5951, Pages 325-488
http://www.sciencemag.org/current.dtl

Policy Forum
Intellectual Property:
Balancing Innovation and Access: Patent Challenges Tip the Scales
Matthew J. Higgins1,* and Stuart J. H. Graham1,2,*

Improvements in pharmaceutical research and development (R&D) depend on product innovation. But the number of new compounds approved annually by the U.S. Food and Drug Administration (FDA) has fallen from an average of 35 in 1996–2001 to 20 in 2002–07 (1). This decline stems from several factors (2); however, one particular U.S. regulation—the Paragraph IV patent challenge—is increasingly stifling new drug innovation and deserves our attention.

1 College of Management, Georgia Institute of Technology, Atlanta, GA 30308, USA.
2 Berkeley Center for Law and Technology, University of California, Berkeley Law School, Berkeley, CA 94720, USA.
* The authors contributed equally to this work.

Vaccine
Volume 27, Issue 45, Pages 6269-6392 (23 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

This issue covers presentations made at ESWI – Third European Influenza Conference
Vilamoura, Portugal, 14-17 September 2008.

Influenza vaccination and mortality benefits: New insights, new opportunities
Pages 6300-6304
Lone Simonsen, Cecile Viboud, Robert J. Taylor, Mark A. Miller, Lisa Jackson

Abstract
Influenza vaccination control strategies in most countries rely on vaccination of seniors and other high risk groups. Although placebo-controlled randomized trials show influenza vaccine is effective in younger age groups, few seniors >70 years were studied even though they suffer >90% of influenza-related deaths. Excess mortality studies could not confirm a national decline in influenza-related mortality while vaccine coverage quadrupled. Cohort studies have consistently reported that vaccination reduces all-cause winter mortality by 50%, an astonishing claim given only 5% of all winter deaths are attributable to influenza. This VE overestimation has now been attributed to profound confounding frailty selection bias. A way forward includes a new generation of unbiased studies with laboratory endpoints, and requires an agreement that the evidence base was flawed. The latter may clear the way for more immunogenic vaccines for seniors and exploration of other influenza control strategies

Challenges in evaluating influenza vaccine effectiveness and the mortality benefits controversy
Pages 6305-6311
Kristin L. Nichol

Abstract
Randomized, controlled trials are the gold standard study design. However, ethical constraints and practical considerations may necessitate other types of studies for evaluating influenza vaccine effectiveness in the elderly—a high priority group for annual vaccination in many countries. Observational studies therefore comprise the bulk of the vaccine effectiveness evidence in older persons, but these types of studies can be susceptible to selection bias and residual confounding. All observational studies should utilize strategies to minimize the impact of bias and confounding. Recent studies questioning the plausibility of reported mortality benefits among vaccinated elderly persons may themselves be based on assumptions that are susceptible to important limitations and multiple biases. Future studies that incorporate prospectively collected information on functional status, life expectancy, and other types of data may provide additional insights into these concerns. At present, even after taking into account the potential for residual bias and confounding, most studies confirm the benefits of vaccination among the elderly for reducing hospitalization and death.

Internet-based monitoring of influenza-like illness in the general population: Experience of five influenza seasons in the Netherlands
Pages 6353-6357
I.H.M. Friesema, C.E. Koppeschaar, G.A. Donker, F. Dijkstra, S.P. van Noort, R. Smallenburg, W. van der Hoek, M.A.B. van der Sande

Abstract
Like in most other countries, influenza surveillance in The Netherlands is based upon influenza-like illness (ILI) consultations reported by sentinel general practitioners (GP). In addition, an internet-based monitoring of ILI in the general population started in 2003/2004 (Great Influenza Survey (GIS)). We compared GIS results over 5 influenza seasons with results from the GP system. Weekly ILI incidence from GIS correlated well with ILI incidence from the GP system the same week and even better 1 week later. This suggests that GIS is useful for early detection of trends in influenza activity. However, two important vulnerable groups, children and the elderly, are clearly underrepresented in the GIS. Furthermore, virological confirmation is lacking in the GIS. So, GIS can be a useful addition to the GP system, especially when representativeness can be improved and when participation remains at the current high level.

Pandemic (H1N1) 2009 – update 69
Weekly update

As of 4 October 2009, worldwide there have been more than 375,000 laboratory confirmed cases of pandemic influenza H1N1 2009 and over 4500 deaths reported to WHO.

As many countries have stopped counting individual cases, particularly of milder illness, the case count is significantly lower than the actually number of cases that have occurred. WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and member states and through monitoring of multiple sources of data.
In the temperate regions of the Northern Hemisphere, transmission of influenza virus and rates of influenza-like-illness (ILI) continue to increase marking an unusually early start to fall and winter influenza season in many countries. Geographically widespread influenza is being reported throughout North America, with the United States reporting ILI levels elevated above the seasonal baseline for the past month and Mexico reporting a high intensity of respiratory diseases for the past three weeks. In Canada, although overall ILI activity remains low, focal increases have been reported in the western part of Canada. In Europe and Central and Western Asia, early transmission of influenza virus continues to increase in many countries, with more intense focal activity being reported in a few. National or regional ILI levels remained elevated above the baseline in parts of the United Kingdom (Northern Ireland and Scotland), Ireland, and Israel. In Ireland, a high intensity of respiratory diseases has been reported for the past two weeks, with the highest rates of ILI reported among children aged 5-14 years old. In addition to Ireland and Israel, widespread geographic spread of influenza virus is also now being reported in Belgium, the Netherlands, and Cyprus. At least 10 countries in the region are also reporting an increasing trend in respiratory diseases activity. In Japan, influenza activity continues to be elevated above the seasonal epidemic threshold since week 33, most recently in the large population centers.
In the tropical regions of the Americas and Asia, influenza virus transmission persists, however influenza activity remained variable. Geographically widespread to regional influenza activity continues to be reported throughout the tropical region of the Americas without a consistent overall trend (and increasing trend in parts of the Caribbean, and decreasing in much of tropical Central and South America). High intensity respiratory diseases activity was reported in Columbia, Cuba, and El Salvador, and moderate healthcare impact was experienced in many countries; two countries, Barbados and St. Lucia, reported severe healthcare impact. As influenza transmission slowly declines in many parts of South and Southeast Asia, several countries are reporting geographically regional spread (India, Bangladesh, and Thailand) or localized spread (Sri Lanka and Myanmar) of influenza activity; and most countries in the region have reported experiencing a low health care impact since late September.
In the temperate regions of the southern hemisphere, influenza transmission has largely subsided (Chile, Argentina, and New Zealand) or continues to decline substantially (South Africa and Australia).
All pandemic H1N1 2009 influenza viruses analyzed to date have been antigenically and genetically similar to A/California/7/2009-like pandemic H1N1 2009 virus. See below for a detailed laboratory surveillance update.

Weekly update (Virological surveillance data)

http://www.who.int/csr/don/2009_10_09/en/index.html

The Weekly Epidemiological Record (WER) for 9 October 2009, vol. 84, 41 (pp 420–436) includes: Recommended composition of influenza virus vaccines for use in the 2010 influenza season (southern hemisphere winter); Antigenic and genetic characteristics of influenza A(H5N1) viruses and candidate vaccine viruses developed for potential use in human vaccines.

http://www.who.int/wer/2009/wer8423.pdf

The U.S. Department of Health and Human Services (HHS) said it is joining with The Ad Council “to launch a series of national television public service advertisements (PSAs) designed to encourage Americans to take steps to protect themselves from the 2009 H1N1 flu virus.” HHS said the ads are designed specifically to reach children, parents, pregnant women and young adults, and that a second series of PSAs, aimed at encouraging high-risk populations to get the H1N1 vaccination, is launching in late October. Included in the PSAs being released are new spots featuring characters from Sesame Street , HHS said.

HHS Secretary Sebelius commented, “While getting a flu vaccine is the best way for Americans to protect themselves and their families from the flu, as we wait for the H1N1 vaccine to get distributed out into local doctors offices and sites across the country, there are critically important things that Americans can be doing right now to keep their friends and family healthy and safe and to prevent the spread of flu. These new prevention PSAs will help us get the word out about what to do about the flu. Fighting the flu is a shared responsibility between all of us and we are so grateful to all those who helped create these wonderful new messages. We are hopeful that Americans will spread these new PSAs virally and use to them to help stop the spread of H1N1 and seasonal flu.”

http://www.businesswire.com/portal/site/home/permalink/?ndmViewId=news_view&newsId=20091008006128&newsLang=en

The NIH said it preparing to launch the first government-sponsored clinical trial to determine what dose of the 2009 H1N1 influenza vaccine is needed to induce a protective immune response in people with asthma, especially those with severe disease. The study is cosponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung, and Blood Institute (NHLBI), both part of NIH. NIAID Director Anthony S. Fauci, M.D. said, “People with severe asthma often take high doses of glucocorticoids that can suppress their immune system, placing them at greater risk for infection and possibly serious disease caused by 2009 H1N1 influenza virus. We need to determine the optimal dose of 2009 H1N1 influenza vaccine that can be safely administered to this at-risk population and whether one or two doses are needed to produce an immune response that is predictive of protection.”

http://www.nih.gov/news/health/oct2009/niaid-09.htm

The MMWR for October 9, 2009 / Vol. 58 / No. 39 includes:
– Influenza Vaccination Coverage Among Children and Adults United States, 2008–09 Influenza Season
In 2008, the Advisory Committee on Immunization Practices (ACIP) recommended all children aged 5-18 years receive seasonal influenza vaccine annually, beginning with the 2008-09 season, if feasible, but no later than the 2009-10 season. To assess vaccination uptake among children and adults during the 2008-09 influenza season, CDC analyzed data from 19 states, representing 43% of the U.S. population. This report summarizes the results of the analysis.
–  Norovirus Outbreaks on Three College Campuses — California, Michigan, and Wisconsin, 2008
–  Update on Influenza A (H1N1) 2009 Monovalent Vaccines
–  Announcement: New System for Monitoring Emergency Department Visits for Influenza-Like Illness

The NIH reported on a NIDA study noting that it “suggests harnessing the immune system against cocaine addiction may prove effective.” In a clinical trial supported by the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health, immunization with an experimental anti-cocaine vaccine resulted in a substantial reduction in cocaine use in 38 percent of vaccinated patients. The study, published in the October issue of the Archives of General Psychiatry, “is the first successful, placebo-controlled demonstration of a vaccine against an illicit drug of abuse.” NIDA Director Dr. Nora Volkow commented, “The results of this study represent a promising step toward an effective medical treatment for cocaine addiction. Provided that larger follow-up studies confirm its safety and efficacy, this vaccine would offer a valuable new approach to treating cocaine addiction, for which no FDA-approved medication is currently available.” NIH said that “like vaccines against infectious diseases such as measles and influenza, the anti-cocaine vaccine stimulates the immune system to produce antibodies. Unlike antibodies against infectious diseases, which destroy or deactivate the disease-causing agents, anti-cocaine antibodies attach themselves to cocaine molecules in the blood, preventing them from passing through the blood-brain barrier. By preventing the drug’s entry into the brain, the vaccine inhibits or blocks the cocaine-induced euphoria.”

http://www.nih.gov/news/health/oct2009/nida-05.htm

Journal of Infectious Diseases
1 November 2009  Volume 200, Number 9
http://www.journals.uchicago.edu/toc/jid/current

Major Articles and Brief Reports
Viruses
Antibody Levels and Protection after Hepatitis B Vaccine: Results of a 22-Year Follow–Up Study and Response to a Booster Dose

Brian J. McMahon, Catherine M. Dentinger, Dana Bruden, Carolyn Zanis, Helen Peters, Debbie Hurlburt, Lisa Bulkow, Anthony E. Fiore, Beth P. Bell, and Thomas W. Hennessy

Background.
The duration of protection in children and adults (including health care workers) resulting from the hepatitis B vaccine primary series is unknown.

Methods.
To determine the protection afforded by hepatitis B vaccine, Alaska Native persons who had received plasma‐derived hepatitis B vaccine when they were >6 months of age were tested for antibody to hepatitis B surface antigen (anti-HBs) 22 years later. Those with levels <10 mIU/mL received 1 dose of recombinant hepatitis B vaccine and were evaluated on the basis of anti‐HBs measurements at 10–14 days, 30–60 days, and 1 year.

Results.
Of 493 participants, 60% (298) had an anti‐HBs level 10 mIU/mL. A booster dose was administered to 164 persons, and 77% responded with an anti‐HBs level 10 mIU/mL at 10–14 days, reaching 81% by 60 days. Response to a booster dose was positively correlated with younger age, peak anti‐HBs response after primary vaccination, and the presence of detectable anti‐HBs before boosting. Considering persons with an anti‐HBs level 10 mIU/mL at 22 years and those who responded to the booster dose, protection was demonstrated in 87% of the participants. No new acute or chronic hepatitis B virus infections were identified.

Conclusions.
The protection afforded by primary immunization with plasma‐derived hepatitis B vaccine during childhood and adulthood lasts at least 22 years. Booster doses are not needed.

The Lancet
Oct 10, 2009  Volume 374  Number 9697  Pages 1213 – 1300
http://www.thelancet.com/journals/lancet/issue/current

Viewpoint
All for universal health coverage

Laurie Garrett, A Mushtaque R Chowdhury, Ariel Pablos-Méndez

Preview
As the USA engages in what promises to be a vibrant debate over how the world’s most costly health-care system can efficiently and equitably provide access to quality health services to all American people, controversies about universal health coverage are brought into high relief, not only in the USA, but also worldwide. Since the mid-20th century, most nations have signed many accords, establishing that provision of health is a fundamental human right;1–4 health for all should be not only an aspirational target but also an essential framework for the United Nations system;5,6 international donor mechanisms should include support for essential health systems and health-workforce development;7,8 poor population health contributes to social and economic instability and undermines development efforts;9 and specific targets for country achievements in health should be set, and funded, through international instruments.

Nature
Volume 461 Number 7265 pp697-836  8 October 2009
http://www.nature.com/nature/journal/v461/n7265/

Editorial
How to win trust over flu

Abstract
Mass-vaccination campaigns for the pandemic H1N1 virus must take public concerns into account.

As countries roll out their campaigns for large-scale vaccination against pandemic H1N1 flu, a poll released last week by the Harvard School of Public Health in Boston, Massachusetts, found that only four in ten US adults have definitely decided to get vaccinated themselves, and just half plan to get the shot for their children (http://go.nature.com/wiB8V3). Harvard’s results parallel those from other surveys, both inside and outside the United States, all of which suggest that many people are still dubious about the vaccine. Public-health authorities, who are keen to contain the pandemic’s spread, need to realize that their best hope of dealing with such public reluctance is to patiently address the concerns that underlie it.

Sometimes, it’s true, those concerns go beyond any appeal to reason. They grow out of a visceral mistrust of authority in general — and of government, regulatory agencies, medical researchers and multinational pharmaceutical companies, in particular. A sophisticated anti-vaccine movement has emerged that plays on this wariness, and helps to feed the conspiracy theories about the H1N1 vaccine that are circulating on the Internet and in viral e-mails.

But far more often, say researchers who have studied this subject, people are assessing vaccination through a perfectly rational cost–benefit analysis. There is a widespread public perception, for example, that the vaccine’s safety trials have been rushed — the Harvard study found that possible side effects were respondents’ main concern — and that H1N1 flu is mild. As a result, many feel no urgent need to be vaccinated, preferring to hold off until they see how the first phases of the vaccination programme go. Indeed, the Harvard poll also found that some 60% of those who don’t intend to get a shot are open to changing their mind if people in their community become severely ill or die.

Such deliberations reflect a perfectly legitimate decision-making process, says Peter Sandman, a risk-communication consultant in Princeton, New Jersey. And governments, he advises, should frame their public-education campaigns in ways that respect people’s judgement and their wait-and-see attitude. Research in risk communication strongly shows that when over-eager officials pressure members of the public who are already skeptical and ambivalent, while being openly dismissive of public concerns, they only end up stoking resistance.

Instead, officials should focus on providing people with the information they need to make good choices for themselves. This should include reminders that coincidences do happen: in any mass- vaccination campaign, at least a few people will fall ill immediately after receiving their shot for reasons that have nothing to do with the vaccine — a possibility vividly highlighted last week by the death of a 14-year-old British girl hours after receiving a vaccine against human papilloma virus. Regulatory authorities need to better explain the extensive safety tests that vaccines undergo and, at the same time, build confidence by being utterly transparent in the reporting and investigation of any suspect events linked to vaccination.

The public-education campaign should also correct the misconception that H1N1 flu is mild. It is mild in most who catch it. But for those individuals — mainly young adults — who will develop the severe form, H1N1 is life-threatening. Moreover, because the virus is new and immunity is lacking, many more people will get it than is typical for seasonal flu, and the toll of serious illness and deaths will accordingly be that much higher.

Finally, people should be reminded that vaccination isn’t just about protecting themselves; it’s also about not spreading the flu to others, which, importantly, alleviates pressure on overstretched hospitals. Campaigns should give altruistic appeals far more prominence than they typically have in the past; research shows that they can be surprisingly effective.

More generally, for officials and researchers at all levels, the skepticism over the pandemic vaccine should serve as a timely reminder of the imperative to work to gain greater public trust in science-based advice and in those who give it.

Vaccine
Volume 27, Issue 44, Pages 6103-6268 (19 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

The cost-effectiveness of rotavirus vaccination: Comparative analyses for five European countries and transferability in Europe
Mark Jit, Joke Bilcke, Marie-Josée J. Mangen, Heini Salo, Hugues Melliez, W. John Edmunds, Yazdanpanah Yazdan, Philippe Beutels

Abstract
Cost-effectiveness analyses are usually not directly comparable between countries because of differences in analytical and modelling assumptions. We investigated the cost-effectiveness of rotavirus vaccination in five European Union countries (Belgium, England and Wales, Finland, France and the Netherlands) using a single model, burden of disease estimates supplied by national public health agencies and a subset of common assumptions. Under base case assumptions (vaccination with Rotarix®, 3% discount rate, health care provider perspective, no herd immunity and quality of life of one caregiver affected by a rotavirus episode) and a cost-effectiveness threshold of €30,000, vaccination is likely to be cost effective in Finland only. However, single changes to assumptions may make it cost effective in Belgium and the Netherlands. The estimated threshold price per dose for Rotarix® (excluding administration costs) to be cost effective was €41 in Belgium, €28 in England and Wales, €51 in Finland, €36 in France and €46 in the Netherlands.

Vaccine
Volume 27, Issue 44, Pages 6103-6268 (19 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

Monitoring adverse events following yellow fever vaccination using an integrated telephone and Internet-based system
Anna P. Durbin, Rosanna Setse, Saad B. Omer, James G. Palmer, Jeffrey A. Spaeder, Judy Baker, Frances Lessans, Neal A. Halsey

Abstract

TeleWatch is an automated telephone/Internet-based system that collects medical product adverse event reports in real-time through an algorithm driven by the patient. 1341 patients, who received yellow fever vaccine and were recruited through 15 travel clinics, contacted the system within 48 h of vaccination and 765 (57%) made follow-up contacts. Participation rates were higher among females and persons older than 60 years of age. TeleWatch can be expanded for use in large campaigns involving influenza or other vaccines.

Vaccine
Volume 27, Issue 44, Pages 6103-6268 (19 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

Mumps resurgences in the United States: A historical perspective on unexpected elements
Albert E. Barskey, John W. Glasser, Charles W. LeBaron

Abstract

In 2006 the United States experienced the largest nationwide mumps epidemic in 20 years, primarily affecting college dormitory residents. Unexpected elements of the outbreak included very abrupt time course (75% of cases occurred within 90 days), geographic focality (85% of cases occurred in eight rural Midwestern states), rapid upward and downward shift in peak age-specific attack rate (5–9-year olds to 18–24-year olds, then back), and two-dose vaccine failure (63% of case-patients had received two doses).

To construct a historical context in which to understand the recent outbreak, we reviewed US mumps surveillance data, vaccination coverage estimates, and relevant peer-reviewed literature for the period 1917–2008.

Many of the unexpected features of the 2006 mumps outbreak had been reported several times previously in the US, e.g., the 1986–1987 mumps resurgence had extremely abrupt onset, rural geographic focality, and an upward-then-downward age shift. Evidence suggested recurrent mumps outbreak patterns were attributable to accumulation of susceptibles in dispersed situations where the risk of endemic disease exposure was low and were triggered when this susceptible population was brought together in crowded living conditions. The 2006 epidemic followed this pattern, with two unique variations: it was preceded by a period of very high vaccination rates and very low disease incidence and was characterized by two-dose failure rates among adults vaccinated in childhood.

Data from the past 80 years suggest that preventing future mumps epidemics will depend on innovative measures to detect and eliminate build-up of susceptibles among highly vaccinated populations.

Vaccine
Volume 27, Issue 44, Pages 6103-6268 (19 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

The potential cost-effectiveness of adding a human papillomavirus vaccine to the cervical cancer screening programme in South Africa
Edina Sinanovic, Jennifer Moodley, Mark A. Barone, Sumaya Mall, Susan Cleary, Jane Harries

Abstract

This study was designed to answer the question of whether a cervical cancer prevention programme that incorporates a human papillomavirus (HPV) vaccine is potentially more cost-effective than the current strategy of screening alone in South Africa. We developed a static Markov state transition model to describe the screening and management of cervical cancer within the South African context. The incremental cost-effectiveness ratio of adding HPV vaccination to the screening programme ranged from US $1078 to 1460 per quality-adjusted life year (QALY) gained and US$3320–4495 per life year saved, mainly depending on whether the study was viewed from a health service or a societal perspective. Using discounted costs and benefits, the threshold analysis indicated that a vaccine price reduction of 60% or more would make the vaccine plus screening strategy more cost-effective than the screening only approach. To address the issue of affordability and cost-effectiveness, the pharmaceutical companies need to make a commitment to price reductions.

Vaccine
Volume 27, Issue 44, Pages 6103-6268 (19 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

Health systems and immunization financing for human papillomavirus vaccine introduction in low-resource settings
Robin Biellik, Carol Levin, Emmanuel Mugisha, D. Scott LaMontagne, Allison Bingham, Satish Kaipilyawar, Sanjay Gandhi

Abstract

This descriptive qualitative study synthesizes health system and immunization financing assessments performed through formative research in India, Peru, Uganda, and Vietnam using a non-probability sample of national and sub-national stakeholders; and recommends appropriate and effective strategies for HPV vaccine delivery in low-resource settings. We conclude that maximum feasibility and acceptability and lowest cost for delivering HPV vaccine can be achieved by implementing through national immunization programs; by partnering with other sectors, such as education and maternal–child health; by strengthening existing human resources and cold chain infrastructures where needed; and finally, by considering schools for reaching the target population.

Vaccine
Volume 27, Issue 44, Pages 6103-6268 (19 October 2009)
http://www.sciencedirect.com/science/journal/0264410X

Modeling the effects of influenza vaccination of health care workers in hospital departments
Abstract

Nowadays health care worker (HCW) vaccination is widely recommended. Although the benefits of this strategy have been demonstrated in long-term care settings, no studies have been performed in regular hospital departments. We adapt a previously developed model of influenza transmission in a long-term care nursing home department to study the effects of HCW vaccination in hospital wards. We study both the effectiveness and efficiency in reducing the hazard rates of influenza virus infection for patients. Most scenarios under study show a similar or higher impact of hospital HCW vaccination than has been predicted for the long-term care nursing home department. Therefore, it seems justified to extend the recommendations for HCW vaccination, based on results in the long-term care setting, to short-term care settings as well.

The WHO continues to issue weekly “updates” and briefing notes as below:

Pandemic (H1N1) 2009 – update 68

Weekly update

As of 27 September 2009, worldwide there have been more than 340,000 laboratory confirmed cases of pandemic influenza H1N1 2009 and over 4100 deaths reported to WHO.

As many countries have stopped counting individual cases, particularly of milder illness, the case count is significantly lower than the actually number of cases that have occurred. WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and member states and through monitoring of multiple sources of data.
Transmission of influenza virus and rates of influenza-like-illness (ILI) continue to increase in the temperate regions of the northern hemisphere. In North America, influenza transmission is geographically widespread and continues to increase. Levels of ILI have continued to increase and remain above the seasonal baseline for the past 4 weeks in most regions of the United States. In Mexico, a high intensity of respiratory diseases has been reported for two consecutive weeks (week 37 – 38), with large increases in cases being reported in the north and northwest of the country. In Europe and Central and Western Asia, although overall influenza activity remains low an increase in transmission has been noted in a number of countries and continues to intensify in others. Rates of influenza-like-illness continue to be above baseline levels in Ireland, parts of the United Kingdom (Northern Ireland), Israel, and France; in addition, more than 10 other countries in the region have reported geographically localized spread of influenza. In Japan, influenza activity has continued to increase above the seasonal epidemic threshold since week 33. These increases in ILI activity have been accompanied by increases in laboratory isolations of pandemic influenza H1N1 2009 in most of these areas.
In the tropical regions of the Americas and Asia, influenza transmission remains active but the trends in respiratory diseases activity are mixed. Although respiratory disease activity is geographically regional to widespread throughout the tropical region of the Americas, many countries have been recently reporting a declining trend (Bolivia, Brazil, Costa Rica, El Salvador, Panama, Paraguay, Venezuela), while others recently reported an increasing trend (Columbia and Cuba). In tropical regions of Asia, there continues to be an increasing trend in respiratory diseases in parts of India and in Cambodia, while other countries in the Southeast Asia have been recently reporting declining transmission.
In the temperate regions of the southern hemisphere, influenza transmission has largely returned to baseline (Chile, Argentina, and New Zealand) or has declined substantially (Australia and South Africa).
All pandemic H1N1 2009 influenza viruses analyzed to date have been antigenically and genetically similar to A/California/7/2009-like pandemic H1N1 2009 virus. See below for a detailed laboratory surveillance update.

Weekly update (Virological surveillance data)

http://www.who.int/csr/don/2009_10_02/en/index.html

GAVI posted information on the efforts of The Global Coalition against Child Pneumonia in advocating for the United Nations to recognize 2 November as World Pneumonia Day. The organizers have set up a website to educate people about pneumonia – www.WorldPneumoniaDay.org – and “are using social media such as Facebook, Twitter, and Change.org to focus attention on pneumonia.”  GAVI said that in the past two weeks, “more than 40 organizations from countries including Bangladesh, Cameroon, the Central African Republic, China, the DRC, India, Jordan, Kenya, Malawi, Mali, Nigeria, the Philippines, Tanzania, Thailand, and Uganda have joined the Global Coalition against Child Pneumonia. This week, the Coalition was also joined by ONE, a global advocacy campaign committed to the fight against global poverty and disease that was cofounded by Bono and other campaigners and is supported by more than 2 million members across the world.”

http://www.gavialliance.org/media_centre/news/2009_10_01_world_pneumonia_day.php

GAVI posted the full text of Mary Robinson’s Viewpoint piece in The Lancet: Realising the human right to health:

WHO declared more than six decades ago that the “enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being”. 1

Nowadays, most countries have ratified international treaties that make the right to health an international legal obligation that has to be progressively realised nationally.

Yet inequalities in basic health services remain intolerably wide, even in many high-income countries. This is despite the fact that health is the fundamental basis of any successful nation: for social cohesion, economic prosperity, and even political stability.

Fortunately, we are seeing a renewed commitment to making access to health care a reality for all. This commitment is evident through the creation of global initiatives that aim to generate broad access to essential health services. One such public—private initiative, the GAVI Alliance (formerly the Global Alliance for Vaccines and Immunisation), was launched in 2000 to finance new and underused vaccines for developing countries that otherwise have no access to these life-saving technologies.

In just under a decade, GAVI Alliance partners have collectively achieved impressive results in 72 of the poorest countries worldwide: vaccines such as those to prevent hepatitis B and Haemophilus influenzae type B infections have now been widely introduced, and hundreds of millions of children have been protected. WHO estimates that, as a result of GAVI Alliance programmes, more than 3·4 million deaths have been averted.2

The case for immunisation is as compelling as ever. Governments worldwide continue to invest in immunisation programmes as a powerful means to protect their populations from disease and save on future health-care expenditures. For developing countries, investment in immunisation is regarded as one of the most cost-effective contributions to their economic development, and an essential way to help realise the right to health for millions of people (figure).

Yet these signs of progress draw attention to further challenges that remain to be addressed. To secure long-term success, more should clearly be done to strengthen the foundations of health systems within countries—eg, by ensuring that health workers with the right training and experience are available in all countries. Realisation of this aim means supporting efforts to make primary and secondary care more accessible, and improving logistics and supply systems so that money, drugs, equipment, and fuel can be made available in the right place at the right time.

With the support of its donors, the GAVI Alliance is contributing to such efforts. It is asking countries to identify restrictions to achieving sustained high immunisation coverage. This goes beyond supply of vaccines and syringes to addressing systemic constraints that are restricting the effectiveness of national health plans. The GAVI Alliance recently welcomed a further commitment to funding for health-system strengthening through an expansion of the International Finance Facility for Immunisation, thanks to support from the UK, Australia, Norway, and the Netherlands.3 The intended use for the additional funds will be to help to address wider maternal and child health issues.

Providing life-saving vaccines to all children worldwide, irrespective of where they live, is fundamental to ensuring the right to health. Global health initiatives such as the GAVI Alliance are crucially important if we are serious about our collective promise. We face many challenges, but must not lose sight of the great opportunities that are within our reach. Only through committed leadership and effective partnerships between the global north and south, between the public and private sectors, and between human rights advocates and health professionals, will we see real progress towards the goal of universal access to health.

I am Chair of the GAVI Alliance Board and President of Realizing Rights: The Ethical Globalization Initiative.

References

1 Constitution of WHO. http://www.who.int/governance/eb/who_constitution_en.pdf. (accessed Sept 24, 2009).
2 WHO. Report on GAVI Progress 2000—2007 and projected achievements 2008—2010, Department of Immunization, Vaccines, and Biologicals. Geneva: World Health Organization, 2008.
3 Outcome document from the meeting of the Taskforce on Innovative International Financing for Health Systems.
http://www.internationalhealthpartnership.net//CMS_files/documents/un_general_assembly_meeting_outcome_document_EN.pdf. (accessed Sept 25, 2009). a Ethical Globalization Initiative, New York, NY 10016, USA

[The Lancet, Volume 374, Issue 9696, Pages 1121 – 1122, 3 October 2009]

http://www.gavialliance.org/media_centre/news/2009_10_03_human_right_to__health_lancet.php

The U.S. Food and Drug Administration issued its Strategic Plan for Risk Communication, which “outlines the agency’s efforts to disseminate more meaningful public health information. The plan also lays out a framework for the FDA to provide information about FDA-regulated products to health care professionals, patients and consumers in the form they need it and when they need it, and for how the agency oversees industry communications.” Commissioner of Food and Drugs Margaret A. Hamburg, M.D. said, “We are committed to improving communications the public receives about the products we regulate. The FDA must communicate frequently and clearly about risks and benefits and inform patients and consumers about ways to minimize risk as they become increasingly involved in managing their health and well-being.” The plan “reflects the FDA’s belief that risk communications must be adapted to the needs of different audiences and should be evaluated to ensure effectiveness. The plan also focuses on improving two-way communication through enhanced partnerships with government and non-government organizations, and focuses on policies that affect areas of high public health impact.”

FDA’s Strategic Plan for Risk Communication

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm184331.htm

The Weekly Epidemiological Record (WER) for 2 October 2009, vol. 84, 40 (pp 405–420) includes: 405 Hepatitis B vaccines; Global Polio Laboratory Network: Fifteenth Annual Informal Consultation. http://www.who.int/wer/2009/wer8440.pdf

The MMWR for October 2, 2009 / Vol. 58 / No. 38 includes:

– Influenza Vaccination Coverage Among Children Aged 6 Months–18 Years — Eight Immunization Information System Sentinel Sites, United States, 2008–09 Influenza Season

– Influenza Vaccination Coverage Among Children Aged 6–23 Months — United States, 2007–08 Influenza Season

– Bacterial Coinfections in Lung Tissue Specimens from Fatal Cases of 2009 Pandemic Influenza A (H1N1) — United States, May–August 2009

The Lancet
Oct 03, 2009  Volume 374  Number 9696   Pages 1119 – 1212
http://www.thelancet.com/journals/lancet/issue/current

Editorial
A (prime) boost for HIV vaccine research?
The Lancet

Preview
“Breakthrough”; “landmark”; “an important day for the planet”. Such were some of the reactions to the news released on Sept 24 that, for the first time, an HIV vaccine has shown a modest degree of efficacy in a phase 3 clinical trial…

The Lancet
Oct 03, 2009  Volume 374  Number 9696   Pages 1119 – 1212
http://www.thelancet.com/journals/lancet/issue/current

Viewpoint
How to maintain surveillance for novel influenza A H1N1 when there are too many cases to count
Marc Lipsitch, Frederick G Hayden, Benjamin J Cowling, Gabriel M Leung

Preview
Surveillance during the present pandemic of influenza A H1N1 (pandemic H1N1) is needed to provide estimates of quantities such as disease incidence and rates of change of incidence, severity of infection, and risks to specific population groups. Estimates of these quantities inform decisions about control measures, resource procurement and allocation, and responses to other public health needs.1 They also affect public perceptions of illness severity and risk, which change the willingness of people to comply with control measures.

Science
2 October 2009  Vol 326, Issue 5949, Pages 1-188
http://www.sciencemag.org/current.dtl

Policy Forum
Public Health:
Rethinking Influenza
Rino Rappuoli,1,* Giuseppe Del Giudice,1 Gary J. Nabel,2 Albert D. M. E. Osterhaus,3 Robin Robinson,4 David Salisbury,5 Klaus Stöhr,6 John J. Treanor7

Today, we are better prepared to face the H1N1 influenza A 2009 virus than we were for any other previous pandemic. Although the present manufacturing capacity is unlikely to have all the vaccines needed before the peak of the next wave of cases, the potential output of vaccine manufacturing has increased from 400 to 900 million (1). A vaccine will be produced in Europe with modern cell culture technology instead of eggs. A large facility for cell culture production under construction in the United States is expected to improve the current limited production capacity. Although vaccines against avian H5N1 are not highly immunogenic, this shortcoming can be overcome by using adjuvants or reverting to using whole-virus vaccines (2–5).

1 Novartis Vaccines and Diagnostics Srl, 53100 Siena, Italy.
2 Vaccine Research Center, National Institute of Allergy and infectious Diseases, NIH, Bethesda, MD 20892–3005, USA.
3 Erasmus University, 3015E Rotterdam, Netherlands.
4 U.S. Department of Health and Human Services (HHS), Washington, DC 20201, USA.
5 World Health Organization (WHO), Strategic Advisory Group of Experts (SAGE) on Immunization, 1211 Geneva 27, Switzerland.
6 Novartis Vaccines and Diagnostics, Inc., Cambridge, MA 02139, USA.
7 University of Rochester, Rochester, NY 14642, USA.

The WHO continues to issue weekly “updates” and briefing notes as below:

Pandemic influenza vaccines: current status: 24 SEPTEMBER 2009 | GENEVA —

Regulatory authorities have licensed pandemic vaccines in Australia, China and the United States of America, soon to be followed by Japan and several countries in Europe. The length of the approval process depends on factors such as each country’s regulatory pathway, the type of vaccine being licensed, and the stage of manufacturers’ readiness to submit appropriate information to regulatory authorities.

Production capacity

In May 2009, WHO estimated that, in a best case scenario, worldwide production capacity for pandemic vaccines would be approximately 5 billion doses per year. Since then, better information on production yield and appropriate vaccine formulation has become available.

WHO currently estimates worldwide production capacity for pandemic vaccines at approximately 3 billion doses per year. While this figure is lower than previously projected, early data from clinical trials suggest that a single dose of vaccine will be sufficient to confer protective immunity in healthy adults and older children, effectively doubling the number of people who can be protected with current supplies.

These supplies will still be inadequate to cover a world population of 6.8 billion people in which virtually everyone is susceptible to infection by a new and readily contagious virus. Global manufacturing capacity for influenza vaccines is limited, inadequate and not readily augmented.

Pandemic vaccines have their greatest impact as a preventive strategy when administered before or near the peak incidence of cases in an outbreak. Both regulatory authorities and vaccine manufacturers have made extraordinary efforts to expedite the availability of vaccines.

Many affluent countries have previously contracted with manufacturers to obtain sufficient vaccine supplies to cover their entire populations. However, most low- and middle-income countries lack the financial resources to compete for an early share of limited supplies. Vaccine supplies in these countries will largely depend on donations from manufacturers and other countries.

Availability in developing countries

Last week, donations of pandemic vaccines for use in developing countries were announced by the United States of America, in concert with Australia, Brazil, France, Italy, New Zealand, Norway, Switzerland and the United Kingdom. Similar support from additional countries is anticipated and warmly welcomed.

WHO will be coordinating the distribution of these donated vaccines. Earlier this year, WHO conducted surveys with its regional and country offices to identify countries that will not have pandemic vaccines unless supplies are donated.

Teams with expertise in field operations, vaccines, and the logistics of their distribution are now working in the JW Lee Centre for Strategic Health Operations (the SHOC room). Initially, they will be distributing an estimated 300 million doses of vaccine to more than 90 countries.

Distribution of the first batches of donated vaccines is expected to begin in November. WHO continues to recommend that health workers be given high priority for early vaccination.

Vaccine safety

National regulatory authorities for medicines carefully examine the known and suspected risks and benefits of any vaccine prior to its licensing. Because the pandemic virus is new, both non-clinical and clinical trials are being conducted to gain essential information on immune response and safety. Outcomes of trials completed to date suggest that pandemic vaccines are as safe as seasonal influenza vaccines.

Side effects are expected to be similar to those observed with seasonal influenza vaccines. Common side effects include local reactions at the injection site (soreness, swelling, redness) and possibly some systemic reactions (fever, headache, muscle or joint aches). In almost all vaccine recipients, these symptoms are mild, self-limited and last 1-2 days.

However, even very large clinical trials will not be able to identify possible rare events that can occur when pandemic vaccines are administered to many millions of people.

WHO advises all countries administering pandemic vaccines to conduct intensive monitoring for safety and to report adverse events. Many countries already have systems for monitoring vaccine safety in place.

International sharing of data from such post-marketing surveillance will be vital in guiding risk-benefit assessments and determining whether changes in vaccination policies are needed. WHO has developed standardized protocols for data collection and reporting in real-time, and will communicate findings to the international community via its web site.

http://www.who.int/csr/disease/swineflu/notes/h1n1_antiviral_use_20090925/en/index.html

Pandemic (H1N1) 2009 briefing note 12

Antiviral use and the risk of drug resistance: 25 SEPTEMBER 2009 | GENEVA –

Growing international experience in the treatment of pandemic H1N1 virus infections underscores the importance of early treatment with the antiviral drugs, oseltamivir or zanamivir. Early treatment is especially important for patients who are at increased risk of developing complications, those who present with severe illness or those with worsening signs and symptoms.[1]

The experience of clinicians, including those who have treated severe cases of pandemic influenza, and national authorities suggests that prompt administration of these drugs following symptom onset reduces the risk of complications and can also improve clinical outcome in patients with severe disease.

This experience further underscores the need to protect the effectiveness of these drugs by minimizing the occurrence and impact of drug resistance. [more at http://www.who.int/csr/disease/swineflu/notes/h1n1_antiviral_use_20090925/en/index.html]

Pandemic (H1N1) 2009 – update 67: 25 September 2009

Weekly update

As of 20 September 2009, there have been more than 300,000 laboratory confirmed cases of pandemic influenza H1N1, 3917 deaths, in 191 countries and territories reported to WHO.

As more and more countries have stopped counting individual cases, particularly of milder illness, the case count is significantly lower than the actually number of cases that have occurred. While the case counts no longer reflect actual disease activity, WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and member states and through monitoring of multiple sources of data.
In the temperate regions of the northern hemisphere, influenza-like-illness (ILI) activity continues to increase in many areas. In North America, the United States has reported continued increases in activity above the seasonal baseline for the last 2 to 3 weeks, primarily in the southeast but now also appearing in the upper midwest and the northeast. In Europe and Central and Western Asia, the United Kingdom is reporting regional increases in ILI activity in Northern Ireland and Scotland and the Netherlands, France, Ireland, and Israel are reporting rates above the seasonal baseline. In Japan, influenza activity continues to be slightly above the seasonal epidemic threshold. The increases in ILI activity have been accompanied by increases in laboratory isolations of pandemic influenza H1N1 2009 in most of these areas.
In the tropical regions of the Americas and Asia, influenza activity remains variable. In parts of India, Bangladesh and Cambodia, influenza transmission continues to be active, while other countries in the Southeast Asia have been recently reporting declining transmission (Indonesia, Singapore and Thailand). Although most countries in the tropical regions of the Americas are still reporting regional to widespread geographic spread of influenza activity, there is no consistent pattern in the trend of respiratory diseases. Peru and Mexico have reported an increasing trend in some areas, while most others are reporting an unchanged or decreasing trend (most notably Bolivia, Venezuela and Brazil).
In the temperate regions of the southern hemisphere, influenza transmission has largely returned to baseline (Chile, Argentina, and New Zealand) or is continuing to decline (Australia and South Africa).
All pandemic H1N1 2009 influenza viruses analyzed to date have been antigenically and genetically similar to A/California/7/2009-like pandemic H1N1 2009 virus. See below for a detailed laboratory surveillance update.

Weekly update (Virological surveillance data)

Systematic surveillance conducted by the Global Influenza Surveillance Network (GISN), supported by WHO Collaborating Centres and other laboratories, continues to detect sporadic incidents of H1N1 pandemic viruses that show resistance to the antiviral oseltamivir. To date, 28 resistant viruses have been detected and characterized worldwide. All of these viruses show the same H275Y mutation that confers resistance to the antiviral oseltamivir, but not to the antiviral zanamivir. Twelve of these drug-resistant viruses were associated with the use of oseltamivir for post-exposure prophylaxis. Six were associated with the use of oseltamivir treatment in patients with severe imunosuppression. Four were isolated from samples from patients receiving oseltamivir treatment. A further two were isolated from patients who were not taking oseltamivir for either treatment or prophylaxis. Characterization of the remaining viruses is under way. Worldwide, more than 10,000 clinical specimens (samples and isolates) of the pandemic H1N1 virus have been tested and found to be sensitive to oseltamivir.
WHO has just concluded its Vaccine Composition Meeting for the Southern Hemisphere (held in Melbourne, Australia) and has made recommendations for the composition of the influenza virus vaccine for use in the 2010 southern hemisphere influenza season. WHO recommends that influenza virus vaccines for use in the 2010 influenza season (southern hemisphere winter) contain the following strains: A/California/7/2009 (H1N1)-like virus; A/Perth/16/2009 (H3N2)-like virus; and B/Brisbane/60/2008-like virus. http://www.who.int/csr/don/2009_09_25/en/index.html

The NIH said that, “In an encouraging development, an investigational vaccine regimen has been shown to be well-tolerated and to have a modest effect in preventing HIV infection in a clinical trial involving more than 16,000 adult participants in Thailand.” Following a final analysis of the trial data, the Surgeon General of the U.S. Army, the trial sponsor, announced that the prime-boost investigational vaccine regimen “was safe and 31 percent effective in preventing HIV infection.” Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) which funded the research, said, “These new findings represent an important step forward in HIV vaccine research. For the first time, an investigational HIV vaccine has demonstrated some ability to prevent HIV infection among vaccinated individuals. Additional research is needed to better understand how this vaccine regimen reduced the risk of HIV infection, but certainly this is an encouraging advance for the HIV vaccine field.”

The Thai Phase III HIV vaccine study, also known as RV144, opened in October 2003. The placebo-controlled trial tested the safety and effectiveness of a prime-boost regimen of two vaccines: ALVAC-HIV vaccine (the primer dose), a modified canarypox vaccine developed by Sanofi Pasteur, based in Lyon, France, and AIDSVAX B/E vaccine (the booster dose), a glycoprotein 120 vaccine developed by Vaxgen Inc., and now licensed to Global Solutions for Infectious Diseases (GSID), based in South San Francisco, Calif. The vaccines are based on the subtype B and E HIV strains that commonly circulate in Thailand. The subtype B HIV strain is the one most commonly found in the United States.

Margaret I. Johnston, Ph.D., director of NIAID’s Vaccine Research Program within the Division of AIDS, said, “The Thai study demonstrates why the HIV vaccine field must take a balanced approach to conducting both the basic research needed to discover and design new HIV vaccines and, when appropriate, testing candidate vaccines in people. Both avenues provide critical information that will continue to help us better understand what is needed to develop a fully protective HIV vaccine.”

NIAID and the collaborating partners are working with other scientific experts to determine next steps, including additional research of the RV144 vaccine regimen and the need to consider the impact of these new findings on other HIV vaccine candidates.

Individuals who acquired HIV infection while participating in the Thai trial have been provided access to HIV care and treatment, including highly active antiretroviral therapy based on the guidelines of the Thai Ministry of Public Health.

http://www.nih.gov/news/health/sep2009/niaid-24a.htm

Merck and QIAGEN N.V announced their intent to collaborate on “a new program to increase access to HPV vaccination and HPV DNA testing in some of the most resource-poor areas of the world.” The companies said the initiative is the first time a vaccine manufacturer and a molecular diagnostics company are collaborating to address the burden of cervical cancer with a comprehensive approach. The commitments of Merck and QIAGEN were highlighted at the annual meeting of the Clinton Global Initiative, and represent a combined value of approximately US$600 million based on current U.S. prices.

The collaboration “will integrate two breakthrough and complementary advances in healthcare” – Merck’s cervical cancer vaccine, GARDASIL and QIAGEN’s digene HC2 HPV DNA Test (called the digene HPV Test) and a new HPV DNA test that is currently in development for use specifically in the developing world. Merck said it intends to provide, for free, up to five (5) million doses of GARDASIL and QIAGEN intends to add to its existing one million test donation program by providing HPV DNA tests to screen an additional 500,000 women. Merck and QIAGEN said they plan to seek other public and private partners “to design and implement national public sector cervical cancer programs, provide treatment as needed, and support improvements in laboratory and vaccine delivery infrastructure, training of healthcare workers, education and advocacy.” The two companies also plan to work with cervical cancer experts to support the development and implementation of sustainable best practice models for cervical cancer reduction in low-income, high disease burden countries.

Margaret G. McGlynn, president, Merck Vaccines and Infectious Diseases, commented, “Nearly every minute of every day a woman is diagnosed with cervical cancer, and many of these women live in developing countries where the burden of the disease is disproportionately high and healthcare infrastructure is limited. We see this collaboration between the two companies as innovative and fundamental to reaching our shared goal of reducing the global burden of cervical cancer.”

Merck and QIAGEN said they plan to reach out to select GAVI-eligible countries to explore the feasibility of implementing cervical cancer reduction programs. These programs are “expected to be national in scope – all girls within a defined age range in the selected countries would be offered vaccination, and the program would work towards implementation of screening – and treatment as needed – for all women of a defined age group.” The participating countries will be announced once program details and implementation strategies have been finalized. http://www.businesswire.com/portal/site/home/permalink/?ndmViewId=news_view&newsId=20090923005684&newsLang=en

The GAVI Alliance “welcomed a series of new financing measures for global health worth up to US$5.3 billion that will save the lives of millions of women and children in developing countries.” GAVI said the innovative financing proposals include US$ 1 billion to expand the International Finance Facility for Immunisation (IFFIm) and “enable substantial new investments in health systems.” The package of new measures were announced at the United Nations in New York at a meeting co-chaired by UK Prime Minister Gordon Brown and World Bank President Robert Zoellick, who “highlighted the need for stronger, better financed health systems, and better access to health services, including immunisation, for women and children.”

http://www.gavialliance.org/media_centre/statements/2009_09_23_IFFIm_HSS_funding.php

PhRMA (Pharmaceutical Research and Manufacturers of America) issued the following statement regarding efforts to enhance transparency in clinical research:

“The PhRMA Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results, which take effect on October 1, 2009, fortify our commitment to patients and healthcare professionals by increasing transparency in clinical trials, enhancing standards for medical research authorship and improving disclosure to manage potential conflicts of interest in medical research.

“Among its key changes, the revised Principles move in lockstep with medical journal editors by adopting the authorship standards of the International Committee of Medical Journal Editors (ICMJE). Under these revised Principles, only individuals who make substantial contributions to medical manuscripts will be recognized as authors.

“What’s more, the strengthened Principles enhance disclosure standards for published research that companies sponsor by also aligning with ICMJE standards regarding disclosure in medical journal manuscripts of all financial or personal relationships that might present a conflict of interest – whether in an article or a letter. Authors of medical journal manuscripts should describe the role of sponsors in designing the study, collecting and interpreting data, and writing the report.

“The revised PhRMA Principles, endorsed unanimously by our member company CEOs, build on improvements already made in the 2004 revision and represent an integral part of our ongoing effort to help ensure objectivity in research and enhance transparency in clinical research.

“PhRMA member companies have a longstanding commitment to ethical conduct of clinical trials and to transparency in reporting. We hope that all companies – including non-PhRMA members – that sponsor clinical research and publish results on websites and in peer-reviewed journals will adopt PhRMA’s standards.

“Other key changes within the revised Principles:

– Increase transparency by committing companies to the timely registration of all interventional clinical trials involving patients – including some early Phase 1 studies – on a public website, to help patients who need medical care enroll in relevant studies. There are important public health benefits associated with making appropriate clinical trial information widely available to healthcare practitioners, patients and others. The most important clinical trials are those that test a medicine in patients – people who actually require medical care. Results of these trials provide medical evidence regarding the safety and effectiveness of medicines in the precise population the medicine is intended to help.

– Greatly expand transparency in medical research by committing to provide results summaries for all interventional clinical trials involving patients – once the medicines are approved or the particular research programs have been discontinued. By providing results summaries of safety and effectiveness data for clinical trials shortly after a drug’s approval or discontinuation of development, PhRMA members will significantly expand the universe of publicly available data about clinical trials in patients.

“In addition, the revisions bring the Principles regarding company-sponsored clinical trial investigator meetings in line with the revised PhRMA Code on Interactions with Healthcare Professionals, which went into effect January 2009.”

http://www.phrma.org/news_room/press_releases/phrma_clinical_trial_principles_strengthen_authorship_standards/

WHO issued a revised position on measles vaccines in routine immunization programmes and recommended vaccination of all children with two doses of measles vaccine as the standard for all national immunization programmes. The second dose can be administered through routine services or given periodically through mass vaccination campaigns to defined age groups. Measles virus is highly infectious, and in the absence of vaccination around 90% of children would suffer infection by ten years of age. Measles can be prevented by vaccination with a safe and effective vaccine. It is often incorporated with rubella, mumps and varicella (chickenpox) vaccines and is equally effective in the single or combined form. In 2007, an estimated 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. http://www.who.int/immunization/newsroom/WHO_position_paper_measles/en/index.html

WHO position paper on measles vaccine [pdf 724kb]

The MMWR for September 25, 2009 / Vol. 58 / No. 37 includes:

– Performance of Rapid Influenza Diagnostic Tests During Two School Outbreaks of 2009 Pandemic Influenza A (H1N1) Virus Infection — Connecticut, 2009

– Updated Recommendation from the Advisory Committee on Immunization Practices (ACIP) for Revaccination of Persons at Prolonged Increased Risk for Meningococcal Disease

The Weekly Epidemiological Record (WER) for 25 September 2009, vol. 84, 39 (pp 397–404) includes: Progress towards measles control in WHO’s African Region, 2001–2008
http://www.who.int/wer/2009/wer8439.pdf

Journal of Infectious Diseases
15 October 2009   Volume 200, Number 8
http://www.journals.uchicago.edu/toc/jid/current

Major Articles and Brief Reports: Bacteria
Cost-Effectiveness of a Potential Prophylactic Helicobacter pylori Vaccine in the United States
Marcia F. T. Rupnow, Alicia H. Chang, Ross D. Shachter, Douglas K. Owens, and Julie Parsonnet

Background.Helicobacter pylori vaccines are under development to prevent infection. We quantified the cost-effectiveness of such a vaccine in the United States, using a dynamic transmission model.

Methods.We compartmentalized the population by age, infection status, and clinical disease state and measured effectiveness in quality‐adjusted life years (QALYs). We simulated no intervention, vaccination of infants, and vaccination of school‐age children. Variables included costs of vaccine, vaccine administration, and gastric cancer treatment (in 2007 US dollars), vaccine efficacy, quality adjustment due to gastric cancer, and discount rate. We evaluated possible outcomes for periods of 10–75 years.

Results.H. pylori vaccination of infants would cost $2.9 billion over 10 years; savings from cancer prevention would be realized decades later. Over a long time horizon (75 years), incremental costs of H. pylori vaccination would be $1.8 billion, and incremental QALYs would be 0.5 million, yielding a cost‐effectiveness ratio of $3871/QALY. With school-age vaccination, the cost-effectiveness ratio would be $22,137/QALY. With time limited to <40 years, the cost-effectiveness ratio exceeded $50,000/QALY.

Conclusion.When evaluated with a time horizon beyond 40 years, the use of a prophylactic H. pylori vaccine was cost-effective in the United States, especially with infant vaccination.

The Lancet Infectious Disease
Oct 2009  Volume 9 Number 10 Pages 583 – 650
http://www.thelancet.com/journals/laninf/issue/current

Leading Edge
Pandemic influenza: the new wave
The Lancet Infectious Diseases

Preview
If the predictions of some experts come to pass, by the time you read this the next wave of pandemic influenza A H1N1 in the northern hemisphere will have begun. Indeed, Ira Longini (University of Washington, Seattle, WA, USA), speaking at the recent Lancet conference on influenza (Beijing, China, August 21–23, 2009) suggested that the peak in cases of H1N1 influenza may have passed by the time that sufficient vaccine is available to reduce the number of people who become ill. Such a scenario rather begs the question of the value of an immunisation programme.