Vaccines and Global Health: The Week in Review :: 24 March 2018

Vaccines and Global Health: The Week in Review is a weekly digest  summarizing news, events, announcements, peer-reviewed articles and research in the global vaccine ethics and policy space. Content is aggregated from key governmental, NGO, international organization and industry sources, key peer-reviewed journals, and other media channels. This summary proceeds from the broad base of themes and issues monitored by the Center for Vaccine Ethics & Policy in its work: it is not intended to be exhaustive in its coverage. You are viewing the blog version of our weekly digest, typically comprised of between 30 and 40 posts below all dated with the current issue date

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 pdf version A pdf of the current issue is available here: Vaccines and Global Health_The Week in Review_24 March 2018

– blog edition: comprised of the approx. 35+ entries posted below.

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– Links:  We endeavor to test each link as we incorporate it into any post, but recognize that some links may become “stale” as publications and websites reorganize content over time. We apologize in advance for any links that may not be operative. We believe the contextual information in a given post should allow retrieval, but please contact us as above for assistance if necessary.

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David R. Curry, MS
Executive Director
Center for Vaccine Ethics and Policy

HHS Secretary Azar to Name Robert R. Redfield, M.D., Director of the Centers for Disease Control and Prevention

Milestones :: Perspectives
HHS Secretary Azar to Name Robert R. Redfield, M.D., Director of the Centers for Disease Control and Prevention
On Wednesday, the Department of Health and Human Services announced that Secretary Alex Azar will name Robert R. Redfield, M.D., as the 18th Director of the Centers for Disease Control and Prevention and Administrator of the Agency for Toxic Substances and Disease Registry.

Upon the announcement, Secretary Azar issued the following statement:
“Dr. Redfield has dedicated his entire life to promoting public health and providing compassionate care to his patients, and we are proud to welcome him as director of the world’s premier epidemiological agency. Dr. Redfield’s scientific and clinical background is peerless: As just one example, during his two-decade tenure at Walter Reed Army Institute of Research, he made pioneering contributions to advance our understanding of HIV/AIDS. His more recent work running a treatment network in Baltimore for HIV and Hepatitis C patients also prepares him to hit the ground running on one of HHS and CDC’s top priorities, combating the opioid epidemic.”

“Furthermore, all of us at HHS are grateful to Dr. Anne Schuchat for her service as Acting Director at CDC, especially during this year’s severe flu season. We look forward to CDC continuing its important work on the opioid epidemic and America’s many other pressing public health challenges.”

Biographical Background
Dr. Robert R. Redfield has been a public health leader actively engaged in clinical research and clinical care of chronic human viral infections and infectious diseases, especially HIV, for more than 30 years.

He served as the founding director of the Department of Retroviral Research within the U.S. Military’s HIV Research Program, and retired after 20 years of service in the U.S. Army Medical Corps. Following his military service, he co-founded the University of Maryland’s Institute of Human Virology with Dr. William Blattner and Dr. Robert C. Gallo and served as the Chief of Infectious Diseases and Vice Chair of Medicine at the University of Maryland School of Medicine.

Dr. Redfield made several important early contributions to the scientific understanding of HIV, including the demonstration of the importance of heterosexual transmission, the development of the Walter Reed staging system for HIV infection, and the demonstration of active HIV replication in all stages of HIV infection.

In addition to his research work, Dr. Redfield oversaw an extensive clinical program providing HIV care and treatment to more than 5,000 patients in the Baltimore/Washington, D.C. community.

Dr. Redfield served as a member of the President’s Advisory Council on HIV/AIDS from 2005 to 2009, and was appointed as Chair of the International Subcommittee from 2006 to 2009.
He is a past member of the Office of AIDS Research Advisory Council at the National Institutes of Health, the Fogarty International Center Advisory Board at the National Institutes of Health, and the Advisory Anti-Infective Agent Committee of the Food and Drug Administration.

JAMA :: Novel Vaccine Technologies – Essential Components of an Adequate Response to Emerging Viral Diseases

Featured Journal Content
Online First – March 22, 2018

Novel Vaccine Technologies – Essential Components of an Adequate Response to Emerging Viral Diseases
Barney S. Graham, MD, PhD; John R. Mascola, MD; Anthony S. Fauci, MD
[free access ]
JAMA. Published online March 22, 2018. doi:10.1001/jama.2018.0345

The availability of vaccines in response to newly emerging infections is impeded by the length of time it takes to design, manufacture, and evaluate vaccines for clinical use. Historically, the process of vaccine development through to licensure requires decades; however, clinicians and public health officials are often faced with outbreaks of viral diseases, sometimes of a pandemic nature that would require vaccines for adequate control. New viral diseases emerge from zoonotic and vectorborne sources, such as Middle East Respiratory Syndrome coronavirus and Chikungunya, and while these diseases are often detected in resource-rich countries, they usually begin in low- and mid-income countries.1 Therefore, part of the timeline for a vaccine involves surveillance and detection of new pathogens in remote areas and transfer of specimens to laboratories capable of vaccine development.

Development of vaccines for viral infections has historically been an empirical and iterative process based on the use of attenuated or inactivated whole virus. This requires unique methods of cultivation for each virus, development of animal models for vaccine testing, and a prolonged process of fine-tuning product formulation and immunogenicity, and for live-attenuated vaccines, pathogenicity. Thus, preclinical vaccine development can take years, followed by several more years of early-phase clinical testing and defining of dose and schedule. Moreover, efficacy testing and registration with regulatory agencies often takes another 5 to 10 years. In total, 15 to 20 years would be a typical timeframe from virus discovery to vaccine availability if the process proceeds smoothly and there are no major biological or logistical challenges.

Fortunately, during the last decade, there have been substantial technological advances for conceiving, developing, manufacturing, and delivering vaccines. Rapid genetic sequencing allows both early identification of new pathogens and the identity of the genes encoding structural proteins that can form the basis for vaccine immunogen development. Also, rapid isolation of human monoclonal antibodies has proven to be extremely helpful in defining epitopes that are the targets of protective immunity.

Additional tools of modern vaccinology include (1) delineation of atomic-level structures of viral proteins that facilitates structure-enabled immunogen design and protein engineering; (2) cell sorting and sequencing technologies that allow single-cell analysis of immune responses; and (3) genetic knock-in technologies that allow construction of animal models with human antibody genes for vaccine testing. These tools have already provided the potential not only for solving long-standing problems in vaccinology, such as the development of a new candidate vaccine for respiratory syncytial virus, but they have facilitated rapid development of new candidate vaccines for emerging pathogens such as the Zika virus and pandemic strains of influenza virus. Synthetic vaccinology and platform manufacturing are important innovations that can speed the initial vaccine immunogen design and vaccine development process, and shorten the time needed for manufacturing and initial regulatory approval to begin phase 1 testing.

Synthetic vaccinology is the process of using viral gene sequence information to accelerate vaccine development.2 For example, if a new influenza virus emerges anywhere in the world and is identified through genomic sequencing, the digitally transferred information can be used to synthesize nucleic acids encoding the viral surface proteins (hemagglutinin and neuraminidase). The process of gene synthesis is now extremely rapid and relatively inexpensive. Thus, within a few weeks, DNA plasmids encoding viral proteins can be available for preclinical testing. These genetic vectors (DNA and mRNA) can be used directly for immunization whereby intramuscular immunization leads to muscle cells producing the viral proteins. Alternatively, the genetic vectors can be used to express recombinant protein antigens, in vitro, that can be used for immunization.

Similarly, if an outbreak of a new flavivirus becomes an epidemic or even a pandemic threat, as with Zika in 2015, the gene sequences that encode the viral surface proteins premembrane and envelope can be rapidly identified and form the basis for vaccine immunogen design strategies, based on prior knowledge of flavivirus structure and mechanisms of neutralization.3 Once a structurally authentic immunogen is available, the protein or genetic vectors encoding the protein can be used to immunize animals. In addition, the vaccine proteins can be used as probes to identify monoclonal antibodies secreted by B cells of convalescent humans. Such antibodies are valuable not only for refining vaccine immunogen designs, but also for development of diagnostic assays and potentially for use in passive transfer as therapeutic agents. Thus, development of reagents, diagnostics, candidate vaccines, and immune assessment assays can be done without having the actual virus in hand. This has particular value for viruses with extreme pathogenicity because it avoids the need for high-level containment in laboratory and manufacturing facilities.

Platform manufacturing technologies allow more rapid production and clinical implementation once the vaccine immunogen design is established. The term platform is used in many ways; however, in vaccine production, it implies that the method for generating and presenting a vaccine immunogen can be applied across multiple pathogens. In essence, the cell substrates, production approach, purification processes, and analytical assays used as release criteria for products made under current Good Manufacturing Procedures are the same even though the immunogen may change. DNA or mRNA nucleic acid vaccines are good examples of how platform manufacturing can shorten timelines from pathogen identification to phase 1 clinical trials.4 DNA vaccine delivery and immunogenicity have evolved and improved over the last 2 decades, making it a viable platform for vaccination.

For DNA plasmid vaccines, the manufacturing process is well established, and their toxicity profile is well understood. The National Institute of Allergy and Infectious Diseases Vaccine Research Center has developed candidate DNA vaccines for several viral disease threats during outbreaks, including SARS coronavirus in 2003, H5N1 avian influenza in 2005, H1N1 pandemic influenza in 2009, and most recently for Zika virus in 2016. Once these pathogens were identified, the time from viral sequence selection to initiation of the phase 1 clinical trial was shortened from 20 months to slightly longer than 3 months (Figure).

Other examples of vaccine platform technologies include viral vector–based approaches where genes encoding viral proteins are incorporated into viral vectors (eg, adenovirus, poxvirus, vesicular stomatitis virus, or paramyxovirus vectors) for gene-based immunogen expression and delivery, or chimeric replication-competent viruses in which the vaccine antigens of one virus are expressed in a common replication-competent virus allowing uniform manufacturing processes (eg, yellow fever or other flavivirus antigens expressed in dengue virus, or human parainfluenza or pneumovirus antigens expressed in bovine parainfluenza or Sendai virus vectors).

Traditional approaches, such as live-attenuated virus vaccines (eg, Sabin polio) or whole-inactivated virus vaccines (eg, Salk polio) would not qualify as platform approaches because the requirements for growth in cell culture and purification are usually different among virus families. Protein-based approaches are also likely to have different requirements for purification and formulation, and they may not be amenable to platform approaches unless the display of proteins on nanoparticles or other carrier systems brings more uniformity to downstream manufacturing approaches. Having a standard manufacturing approach reduces the time needed for current Good Manufacturing Procedures process development and simplifies regulatory approval because the safety database that has accumulated for a given platform can be applied to multiple vaccine products.

In summary, emerging viral diseases with pandemic potential are a perpetual challenge to global health. The time-honored approach to vaccinology, which depends predominantly on isolating and growing the pathogen, has not adequately met this challenge. To effectively prepare for and respond to these continually emerging threats, it will be critical to exploit modern-day technological advances, preemptively establish detailed information on each family of viral pathogens, and invest in more infrastructure for surveillance in developing countries to expedite pathogen identification and jump-start the process of vaccine development using these new technologies.2 Failure to do so will result in the untenable situation of not optimally using vaccinology in the response to newly emerging infectious disease threats.

[References available at title link above]

World TB Day – WHO :: NIH Statement on World Tuberculosis Day 2018

World TB Day, 24 March 2018
:: Fact sheet
:: Wanted: Leaders for a TB-free world
23 March 2018 – The theme of World TB Day 2018 is “Wanted: Leaders for a TB-free world”. The day focuses on building commitment to end TB, not only at the political level with Heads of State and Ministers of Health, but at all levels from Mayors, Governors, parliamentarians and community leaders, to people affected with TB, civil society advocates, health workers, doctors or nurses, NGOs and other partners. All can be leaders of efforts to end TB in their own work or terrain.

NIH Statement on World Tuberculosis Day 2018
Statement of Christine F. Sizemore, Ph.D., Richard Hafner, M.D., and Anthony S. Fauci, M.D.
Friday, March 23, 2018
[Editor’s text bolding]
In the 130 years since the discovery of Mycobacterium tuberculosis (Mtb) — the bacterium that causes tuberculosis (TB) — at least 1 billion people have died from TB. That death toll is greater than the combined number of deaths from malaria, smallpox, HIV/AIDS, cholera, plague and influenza. Today, in commemoration of World TB Day, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), renews and reinvigorates its commitment to the research needed to end this ancient scourge.

Mtb is transmitted through the air and primarily affects the lungs.  TB is the leading killer among infectious diseases and among the top 10 causes of death worldwide.  The World Health Organization (WHO) estimates that in 2016, TB claimed the lives of 1.7 million people, including 250,000 children, and 10.4 million people were newly infected with Mtb. TB is the primary cause of death for individuals co-infected with HIV. According to the WHO, more than 2 billion people globally are “latently” infected with TB, meaning they carry the bacteria but are currently without symptoms, which would include cough, fever, weight loss and night sweats. People with latent TB infection cannot actively transmit TB bacteria to another person. Up to 13 million people in the United States are estimated to have latent TB infection, according to the U.S. Centers for Disease Control and Prevention. Overall, people with latent TB infection have a 5 to 15 percent lifetime risk of developing active TB disease. This risk increases for people with compromised immune systems, such as those living with HIV, people receiving immunosuppressive therapy (such as individuals being treated for cancer), as well as diabetics, smokers and the malnourished.

WHO’s End TB Strategy envisions an end to TB by 2035. To accomplish this, incremental improvements in understanding the disease and in the tools used to identify, treat, and prevent it will not be sufficient. Rather, accelerated efforts and transformative advances are needed. Recent engagement includes NIAID participation in the first “WHO Global Ministerial Conference on Ending TB in the Sustainable Development Era: A Multisectoral Response” in Moscow. At this November 2017 meeting, the urgent need for a more intensive biomedical research approach to controlling and ultimately eliminating TB was clearly articulated. Specifically, we need a more intensive interdisciplinary systems biology approach (using cutting-edge methods, large data sets, and modeling to understand complex biological systems) to improve our understanding of how Mtb infection causes disease. Additionally, we must work toward improved diagnostics that can detect Mtb in a variety of clinical specimens in addition to sputum. Also, rapid, accurate, and inexpensive “point-of-care” tests to distinguish between drug-sensitive and drug-resistant Mtb must be developed. NIAID investments in research contributed substantially to the WHO-endorsed GeneXpert MTB/rifampicin resistance diagnostic currently in use, and the Institute continues to support the development of next-generation TB diagnostics.

Today’s treatment regimens for TB require too many drugs, often with toxic side effects, that must be taken for six months or longer. With the increasing incidence of multidrug resistant TB (MDR-TB), these regimens often become very lengthy (up to 20 months), more complex, costly, and more prone to failure. Extensively drug-resistant TB (XDR-TB) is even more difficult to treat, and for some patients, no effective treatment regimens exist. Despite the urgent need for new and improved TB treatments, there is a paucity of new drugs in the clinical development pipeline. To address this deficit, NIAID-supported investigators have engaged in cross-disciplinary, international collaborations designed to spur basic science and early-stage TB drug discovery. Additionally, NIAID has used its HIV/AIDS clinical trials networks to enhance TB clinical research by conducting key studies of potential TB treatment strategies. For example, a NIAID-led study found that a one-month antibiotic regimen to prevent active TB disease in people with latent TB infection was as safe and effective as the standard 9-month course in people living with HIV.  Additionally, the NIAID-funded HIV/AIDS clinical trials networks have conducted studies of improved regimens for MDR-TB therapeutics geared to treat both HIV-infected and uninfected adults and children.

A broadly effective preventive TB vaccine could avert millions of new Mtb infections; however, critical knowledge gaps have made developing such a vaccine a difficult challenge. The current Bacille Calmette-Guerin (BCG) vaccine, developed in 1921, offers protection against disseminated TB disease and death in children, but this protection does not reliably extend into adulthood.  A recent study suggests that revaccination with the vaccine could potentially prevent Mtb infections in high-risk adolescents. To reliably protect against the transmissible pulmonary form of the disease in adults, a new, more effective intervention strategy is needed. NIAID supports basic, preclinical and clinical research to find and develop new, innovative vaccines to prevent TB infection and disease.

The WHO estimates that 53 million lives were saved between 2000 and 2016 through improved TB diagnosis and treatment. Through an intensified research agenda, a sustained commitment to supporting and conducting TB research, and a renewed effort to work with other agencies and organizations, NIAID is dedicated to helping eliminate this disease and improving and saving the lives of people with TB. In September 2018, the United Nations General Assembly will conduct a high-level meeting on TB—representing an important step forward by governments and other partners from around the world in the fight against TB. On this World TB Day, we stand with global leaders in response to the bold call of action to make history and end TB.

Anthony S. Fauci, M.D., is Director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health in Bethesda, Maryland. Richard Hafner, M.D., is chief of the TB Clinical Research Branch in NIAID’s Division of AIDS; Christine F. Sizemore, Ph.D., is chief of the Tuberculosis and other Mycobacterial Diseases Section in the NIAID Division of Microbiology and Infectious Diseases.
   NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website

PLoS Medicine :: Time for high-burden countries to lead the tuberculosis research agenda

Featured Journal Content

PLoS Medicine
(Accessed 24 March 2018)

Time for high-burden countries to lead the tuberculosis research agenda
Madhukar Pai
| published 23 Mar 2018 PLOS Medicine

At long last, tuberculosis (TB) is getting the political attention that it deserves, being the leading infectious killer of humans today. In 2016, there were 10.4 million estimated new TB cases, with over 1.7 million deaths [1]. The G20 declaration of July 2017 included TB in the context of the need to respond to the antimicrobial resistance threat, following the group’s meeting in Hamburg, Germany [2]. In November 2017, for the first time, a WHO Global Ministerial Conference on TB was held in Moscow, Russia, culminating in the Moscow Declaration to End TB [3]. This year, in September, the United Nations General Assembly (UNGA) will hold the first-ever high-level meeting on the fight against TB [4].

While the political attention brings much needed hope, other developments provide cause for worry. The United States government, the largest funder of TB control and research, is rapidly scaling back on overseas aid, slashing billions from global health and humanitarian assistance [5]. Canada, despite its progressive policies, is spending substantially less on international aid than comparable G7 countries [6]. And while there are considerable uncertainties, Brexit could have a major impact on European Union international development and humanitarian policies and is expected to challenge the EU’s role as the world’s leading donor [7].

The case for funding global health in general, and TB in particular, in this political climate will lack for attention as long as wealthy donor countries focus their priorities on populist and nationalist demands or short-term outcomes of a transactional nature. It is therefore critical for countries most affected by TB to step up, show leadership, and invest in TB control as well as research.

Take the case of Brazil, Russia, India, China, and South Africa (BRICS), which together account for 46% of all incident cases of TB and 40% of all TB-related mortality [1]. With strong, if uneven, economic growth in BRICS, and their growing stature and leadership in the political arena, these countries are well placed to lead the charge against a disease that is a leading killer of their citizens and a huge drain on their economies [8]. In fact, investments in TB control can lead to a huge return on investments for these countries [9].

Commendably, there are signs of the BRICS stepping up to deal with TB, commensurate with their disease burden and economic and scientific prowess [8]. The BRICS Leaders Xiamen Declaration (2017) specifically mentioned the need to improve surveillance of TB and also agreed to set up a TB research network [10].

In fact, the BRICS are now major producers of TB research [11]. While the US remains the top producer of TB research in the past 2 decades, India and China have emerged as the second and third leading producers of TB research in recent years [11]. Further, bibliometric analyses show that the average year-on-year increase in TB publications from the BRICS countries was, in the past decade, nearly double the overall year-on-year increase across all countries [11].

Russia showed leadership in hosting the Global Ministerial Conference, while South Africa has shown commendable initiative in scaling up access to antiretrovirals, as well as new TB diagnostics and drugs (e.g., bedaquiline), and by launching an ambitious National Strategic Plan and 90-90-90 targets to control the linked epidemics of TB and HIV.

Brazil, China, and India have made strong moves to lead on the TB research agenda. In 2015, Brazil established its National TB Research Strategy. In 2016, India launched an India TB Research Consortium to develop new tools for TB and advance evidence-based TB control policies and has increased domestic investments in TB research funding, to align with its National Strategic Plan to Eliminate TB (2017–2025). China is today among the top 5 largest funders of TB research [11]. By making huge domestic investments in science and technology research, China recently overtook the US in terms of total number of science publications [12].

With regards to new tools, both India and China have successfully developed rapid molecular TB tests, using indigenous, more affordable technology platforms, and South Africa is leading the way in vaccine research and clinical trials of new biomarkers as well as TB drug regimens.

While there is evidence of good collaborations between the BRICS and high-income countries (e.g., Indo-US or South Africa-UK collaborations), data suggest that collaborations among BRICS countries are not common [11]. This opportunity must be grasped. As proposed by the BRICS leaders, and reiterated in the Moscow declaration, a TB research network funded and managed by BRICS would go a long way in enhancing collaborations among these countries, improving exchange of technologies and best practices, facilitating multicentric trials of new tools, and avoiding duplication of research efforts.

Along the lines of the BRICS, there is a need for other coalitions of high-burden countries to step up. About 25% of the global incident cases occur in the WHO African Region, with the proportion of TB cases coinfected with HIV exceeding 50% in parts of southern Africa [1]. In this context, the African Union, which consists of all 55 countries on the African continent, is well placed to take leadership on the TB-HIV coepidemic response.

Eliminating TB will not be possible without new tools and approaches. In the Moscow Declaration to End TB, more than 120 national delegations committed to developing and implementing more ambitious, fully funded national TB policies and strategic plans, including for TB research, that are aligned with national health plans and consistent with the End TB Strategy [3]. It is critical that all stakeholders work together to make this declaration a reality and hold political leaders accountable for their pledges, especially their commitment to increased domestic funding to ensure quality TB care and social protection for the most vulnerable sections of the population.

The world cannot depend on a few wealthy countries with very low TB incidence to support all the research that is required to tackle TB. High-burden, middle-income countries with high TB rates must step up. They have the potential to transform the global TB research agenda through increased domestic funding, collaborative networks, and transnational research partnerships. By taking the lead on TB research, high-burden countries not only can meet their own national strategic plan goals but can also take a leading step towards fulfilling the commitment to end the TB epidemic, with targets to reduce TB deaths by 95% and to reduce TB incidence rate by 90% between 2015 and 2035.
[References available at title link above]

Dengvaxia :: WHO laments low vaccination rates in Philippines amid Dengvaxia scare


WHO laments low vaccination rates in Philippines amid Dengvaxia scare
Published March 22, 2018 9:37pm
The World Health Organization has expressed concern over reports coming from the Department of Health citing low vaccination rates due to the scare brought about by the Dengvaxia controversy.

WHO Country Representative to the Philippines Gundo Weiler said anxiety over the reported ill-effects of the anti-dengue vaccine should not prevent parents from having their children vaccinated against preventable diseases like polio, hepatitis, measles, tuberculosis and the mumps.

“We have to remember this is a very different situation. This cannot be compared to the routine vaccination program that the Philippines has been running for many, many years which has been a very safe and very effective vaccination program,” said Weiler, referring to at least six vaccines given for free by the Department of Health as part of its standard immunization program…

Weiler says the 2014 measles outbreak in the country where an estimated 58,000 and 110 deaths were reported, is one unfortunate result if vaccination targets are not met.
The Department of Health is encouraging parents to have their children vaccinated before the onset of the summer break where, traditionally, outbreak of measles and chicken pox are prevalent.

Health Undersecretary Eric Domingo called on parents to trust other vaccines that have been regularly administered by the DOH over the past several decades.

“Naiintindihan naman natin na nagkaroon sila ng konting pangamba. Hindi siya katulad ng Dengvaxia na bagong bago na nagamit sa maramihan,” Domingo said.

The DOH had previously scored the findings of the Public Attorney’s Office hinting of possible links between the Dengvaxia vaccine and the deaths of at least 30 children.

The PAO has filed a civil case against drug maker Sanofi Pasteur and former DOH Officials for the death of an 11 year old child, using evidence gleaned from tissue samples and forensic examinations.

A similar study undertaken by the expert panel led by pathologists and other experts from the UP-PGH has yet to find evidence linking Dengvaxia to any of the suspected vaccine-related deaths.

To counter the falling vaccination rates in the country, some local government health workers like those in Zamboanga City, are waging a house to house vaccination campaign.

Around 230 suspected cases of measles have been reported in the city with around 5 deaths attributed to the disease.

Data from the City Health Office indicates only around 60 percent of an estimated 110 thousand children aged 6 to 56 months old have received the measles vaccine…

Health workers in Barangay Roxas are also doing a house to house vaccination campaign this summer and have not reported any incident where parents did not agree to have their children vaccinated. —JST, GMA News


Lancet Infectious Diseases: Cholera control: one dose at a time :: Efficacy of a single-dose regimen of inactivated whole-cell oral cholera vaccine: results from 2 years of follow-up of a randomised trial

Featured Journal Content

Lancet Infectious Diseases
Available online 14 March 2018
In Press, Corrected ProofNote to users

Cholera control: one dose at a time
Louise C Iversa, b,
Open Access
Cholera continues to harm the most vulnerable people worldwide.1 As an indicator of human progress, the sustained or new presence of the disease in any region is a stark reminder of how far we, as a society, have to go to reach Sustainable Development Goal 6: ensuring availability and sustainable management of water and sanitation for all.2 Diarrhoeal diseases are a major source of preventable morbidity and mortality, and in 2015 claimed the lives of more than 1·3 million people, of whom 499,000 were children younger than 5 years.3

As a contributor to the global burden of diarrhoeal disease, Vibrio cholerae is a particularly harsh pathogen, causing rapid onset of severe nausea, vomiting, and profuse watery diarrhoea that can lead to death within hours—even of the healthiest young adults. Whole communities can be rapidly affected in epidemics, causing both physical harm and psychological distress. The pervasive social determinant of the problem—poor or no access to safe water, sanitation, and hygiene—means that displaced people, refugee populations, and those in conflict zones are at risk of major outbreaks of the illness. Cholera also continues to occur routinely, regularly, and with great impact (although often with less media attention) in endemic countries, such as Bangladesh and now Haiti, where children and the poorest people are the most at risk of being harmed. In both epidemic and endemic circumstances, the public health role of cholera vaccination has been re-emerging with interest from policy makers over the past 8 years.

In The Lancet Infectious Diseases, Firdausi Qadri and colleagues 4 describe results of 2 years of follow-up of a large, randomised, double-blind, placebo-controlled efficacy trial of a single dose of an inactivated whole-cell oral cholera vaccine (OCV) in Bangladesh. They found that a single dose provided protection for at least 2 years when given to adults (vaccine protective efficacy against all cholera episodes 59%, 95% CI 42–71) and to children aged 5 years or older (52%, 8–75). The findings make an important contribution to cholera control around the world, and could help to take us one step closer to WHO’s ambitious goal of reducing deaths from the disease by 90% by 2030.5

Increasing practical experiences with large-scale public health use of OCV—initially including reactive vaccination campaigns in Guinea and Haiti in 2012,6 ;  7 revitalised WHO’s support of cholera-affected countries,8 and investment by GAVI, the vaccine alliance, in a global stockpile of vaccine—have resulted in millions of doses of OCV being used each year since 2014. The vaccine has most often been given in two doses, 14 days apart, as recommended by the manufacturers.9 Yet giving a second dose of OCV on schedule can be challenging during crisis situations. Furthermore, multiple competing demands on the global stockpile mean that, at times, officials might have to decide if they should vaccinate a population without guarantee of the availability of the second tranche of doses.

Qadri and colleagues’ trial complements findings from other important studies on the use of a single-dose OCV, which were largely secondary analyses and shorter-term prospective observational studies.10 ;  11 Together, the evidence shows that single-dose OCV campaigns can be effective both in the short term in outbreaks and for up to 2 years in endemic settings. With these data to further support decision making on who to vaccinate against cholera and when to vaccinate them, government agencies, multilateral organisations, and non-governmental organisations should continue to invest in cholera vaccines as a part of the toolkit to control and prevent the disease.

However, a single dose of OCV did not protect children younger than 5 years compared with placebo (vaccine protective efficacy against all cholera episodes −13%, 95% CI −68 to 25),4 consistent with the 6-month results of the same study.12 Other studies show some, but reduced, protection of two doses of OCV in this age group as well, which has implications for strategies on the use of OCV in highly endemic regions where young children are an important risk group.13 Further studies are needed to determine how best to protect the youngest individuals, and to identify the ideal dosing schedule of the vaccine.

Still more evidence is needed on how to integrate vaccination strategies into evidence-based water, sanitation, and hygiene interventions to interrupt diarrhoeal disease—a subject in which evidence of impact is surprisingly scarce.14 What is notable about the discourse on OCV in 2018 are the burning questions not associated with whether vaccines should be used in endemic countries or whether they should be used during epidemics for cholera control, but rather how best to use them in a way that maximises effectiveness and efficiency in saving the lives of the most vulnerable people from this entirely preventable disease.


Available online 14 March 2018
In Press, Corrected Proof — Note to users
Efficacy of a single-dose regimen of inactivated whole-cell oral cholera vaccine: results from 2 years of follow-up of a randomised trial
Firdausi Qadri, PhDa, Mohammad Ali, PhDb, Julia Lynch, MDc, Fahima Chowdhury, MPHa, Ashraful Islam Khan, PhDa, Thomas F Wierzba, PhDd, Jean-Louis Excler, MDc, Amit Saha, MMeda, Md Taufiqul Islam, MPHa, Yasmin A Begum, PhDa, Taufiqur R Bhuiyan, PhDa, Farhana Khanam, MSca, Mohiul I Chowdhury, MPHa, Iqbal Ansary Khan, MPHe, Alamgir Kabir, MSca, Prof Baizid Khoorshid Riaz, MPHf, Afroza Akter, MPHa, Arifuzzaman Khan, MBBSa,
A single-dose regimen of inactivated whole-cell oral cholera vaccine (OCV) is attractive because it reduces logistical challenges for vaccination and could enable more people to be vaccinated. Previously, we reported the efficacy of a single dose of an OCV vaccine during the 6 months following dosing. Herein, we report the results of 2 years of follow-up.
In this placebo-controlled, double-blind trial done in Dhaka, Bangladesh, individuals aged 1 year or older with no history of receipt of OCV were randomly assigned to receive a single dose of inactivated OCV or oral placebo. The primary endpoint was a confirmed episode of non-bloody diarrhoea for which the onset was at least 7 days after dosing and a faecal culture was positive for Vibrio cholerae O1 or O139. Passive surveillance for diarrhoea was done in 13 hospitals or major clinics located in or near the study area for 2 years after the last administered dose. We assessed the protective efficacy of the OCV against culture-confirmed cholera occurring 7–730 days after dosing with both crude and multivariable per-protocol analyses. This trial is registered at, number NCT02027207.
Between Jan 10, 2014, and Feb 4, 2014, 205,513 people were randomly assigned to receive either vaccine or placebo, of whom 204,700 (102,552 vaccine recipients and 102,148 placebo recipients) were included in the per-protocol analysis. 287 first episodes of cholera (109 among vaccine recipients and 178 among placebo recipients) were detected during the 2-year follow-up; 138 of these episodes (46 in vaccine recipients and 92 in placebo recipients) were associated with severe dehydration. The overall incidence rates of initial cholera episodes were 0·22 (95% CI 0·18 to 0·27) per 100,000 person-days in vaccine recipients versus 0·36 (0·31 to 0·42) per 100,000 person-days in placebo recipients (adjusted protective efficacy 39%, 95% CI 23 to 52). The overall incidence of severe cholera was 0·09 (0·07 to 0·12) per 100,000 person-days versus 0·19 (0·15 to 0·23; adjusted protective efficacy 50%, 29 to 65). Vaccine protective efficacy was 52% (8 to 75) against all cholera episodes and 71% (27 to 88) against severe cholera episodes in participants aged 5 years to younger than 15 years. For participants aged 15 years or older, vaccine protective efficacy was 59% (42 to 71) against all cholera episodes and 59% (35 to 74) against severe cholera. The protection in the older age groups was sustained throughout the 2-year follow-up. In participants younger than 5 years, the vaccine did not show protection against either all cholera episodes (protective efficacy −13%, −68 to 25) or severe cholera episodes (−44%, −220 to 35).
A single dose of the inactivated whole-cell OCV offered protection to older children and adults that was sustained for at least 2 years. The absence of protection of young children might reflect a lesser degree of pre-existing natural immunity in this age group.
Bill & Melinda Gates Foundation to the International Vaccine Institute.