WHO – SAGE meeting, Nov 2013

WHO: Strategic Advisory Group of Experts (SAGE) on Immunization
The next SAGE meeting will take place n Geneva on 5-7 November 2013.
Draft agenda (as of 17 October 2013)
Selected Agenda Topics (excerpt):
:: Global polio eradication initiative – Session 4
For decision:
–       Optimal schedule for 1 IPV dose
–       Strategic framework for responding to type 2 virus detection post-OPV2 cessation
–       Recommendation for a WHA resolution in 2014 on accelerated IPV introduction, based on the progress toward a global supply and financing strategy

For discussion:
–       Strategy to ensure bOPV access to all OPV-using countries

:: Decade of Vaccines – Global Vaccine Action Plan (GVAP) Monitoring – Session 5
For Decision
SAGE will be expected to produce an independent first report on progress with the Decade of Vaccines Global Vaccine Action Plan.
Specifically, SAGE will be asked to:
– Review the DoV WG “Assessment report on DoV progress” based on:
– the review of the “annual report on the Decade of Vaccines progress” prepared by the DOV secretariat,
– Information provided by other partners’ annual reports on Decade of Vaccines progress.

– Make recommendations on any necessary changes to the formulation of the indicators, operational definitions and/or the processes for data collection.

– Identify successes, challenges and areas where additional efforts or corrective actions by countries, regions, partners, donor agencies or other parties, are needed.

– Provide recommendations and corrective actions for Members States, regions, partners, donor agencies or other parties regarding DoV GVAP implementation in a “SAGE Assessment report on the Decade of Vaccines progress” which will be the basis of the “progress report” for the WHO Board and World Health Assembly.

:: Measles and rubella elimination – Session 7
For discussion:
–       Global status report
–       Report from each Region
–       How to get back on track towards global and Regional targets

For decision:
–        Use of combined measles-rubella vaccine for both routine doses
–        Criteria to guide countries on expansion of the target age range measles and measles-rubella SIAs

For decision:
–        Vaccination of health workers

.
:: Smallpox vaccines – Session 8

For decision
:: The last case of Smallpox occurred in 1977. In 1980 the World Health Assembly declared this disease eradicated. A global stockpile of vaccines, held in Switzerland, was created with donations from Member States.

:: In 2004 Previous the Ad-Hoc Orthopoxvirus Committee, recommended that the stockpile should consist 200 million doses. The current physical WHO stockpile is ~ 2.4 million doses, and the virtual stockpile consists of 31 million doses.

:: In order for WHO to make an informed decision (risk-benefit) on which vaccines to stock and to be able to give advice to countries on their stockpile, WHO would like SAGE to answer the following questions:
–  Which vaccine should be recommended to be used during an outbreak of smallpox? (vaccine used during the eradication, vaccine produced in tissue cell, or further attenuated vaccines).
– Composition of stockpile
–Size of stockpile

–       What groups should be prioritized to be vaccinated while faced with limited vaccine supply?
–Age groups, risk factors/safety aspects, vulnerable populations, ethical considerations

–Which vaccine should be given?

–       Which vaccine should be recommended for preventive use?

–       Who should be targeted and with which immunization schedule? (First aid responders, army, police, health workers)

WHO: Global tuberculosis report 2013

WHO: Global tuberculosis report 2013
http://www.who.int/entity/tb/publications/global_report/en/index.html
–       Gains in tuberculosis control at risk due to 3 million missed patients and drug resistance
–       Progress in TB control can be substantially accelerated by addressing these challenges

Excerpt from media release
…The new data confirm that the world is on track to meet the 2015 UN Millennium Development Goals (MDGs) target of reversing TB incidence, along with the target of a 50% reduction in the mortality rate by 2015 (compared to 1990). A special “Countdown to 2015” supplement to this year’s report provides full information on the progress to the international TB targets. It details if the world and countries with a high burden of TB are “on-track” or “off-track” and what can be done rapidly to accelerate impact as the 2015 deadline approaches.

Key challenges
The report underlines the need for a quantum leap in TB care and control which can only be achieved if two major challenges are addressed.
–       Missing 3 million – around three million people (equal to one in three people falling ill with TB) are currently being ‘missed’ by health systems.
–       Drug-resistant TB crisis – the response to test and treat all those affected by multidrug-resistant TB (MDR-TB) is inadequate.

Insufficient resources for TB are at the heart of both challenges. TB programmes do not have the capacity to find and care for people who are “hard-to-reach”, often outside the formal or state health system. Weak links in the TB chain (a chain that includes detection, treatment and care) lead to such people being missed…

…Five priority actions
The WHO report recommends five priority actions that could make a rapid difference between now and 2015.
–       Reach the 3 million TB cases missed in national notification systems by expanding access to quality testing and care services across all relevant public, private or community based providers, including hospitals and NGOs which serve large proportions of populations at risk.
–       Address with urgency the MDR-TB crisis. Failure to test and treat all those ill with MDR-TB carries public health risks and grave consequences for those affected. High-level political commitment, ownership by all stakeholders, adequate financing and increased cooperation are needed to solve bottlenecks in drug supply and build capacity to deliver quality care.
–       Intensify and build on TB-HIV successes to get as close as possible to full antiretroviral therapy (ART) coverage for people co-infected with TB and HIV.
–       Increase domestic and international financing to close the resource gaps – now estimated at about US$ 2 billion per year – for an effective response to TB in low- and middle-income countries. Full replenishment of the Global Fund is essential, given that most low-income countries rely heavily on international donor funding, with the Global Fund providing around 75% of financial resources in these countries.
–       Accelerate rapid uptake of new tools – through technology transfer and operational research to ensure that countries and communities most at risk benefit from these innovations.

http://www.who.int/mediacentre/news/releases/2013/tuberculosis-report-2013/en/index.html

HPV vaccine: safety, adverse events

British Medical Journal
26 October 2013 (Vol 347, Issue 7930)
http://www.bmj.com/content/347/7930

Editorial
Safety of the quadrivalent human papillomavirus vaccine
BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f5631 (Published 9 October 2013
Now well established
The prophylactic human papillomavirus (HPV) vaccines are remarkable both for their efficacy against HPV infection and related diseases,1 and for their potential to prevent cervical cancer. Cervical cancer, which is caused by persistent infection with oncogenic HPV types, remains a cause of premature death in women around the world, most of whom have no access to secondary prevention through organised cervical screening programmes.2 The linked study by Arnheim-Dahlström and colleagues (doi:10.1136/bmj.f5906) provides a timely and important contribution to the evidence base on the safety of the quadrivalent HPV vaccine,3 which prevents HPV infection and disease due to the oncogenic types HPV-16 and HPV-18 and types HPV-6 and HPV-11, which cause genital warts.

This population based cohort analysis provides strong evidence that autoimmune conditions, neurological diseases, and thromboembolic disease are not triggered by quadrivalent HPV vaccination. Serious sudden onset conditions such as these, which are largely of undetermined cause, are sometimes falsely attributed to vaccination when population based vaccination programmes are implemented.4 It is crucial that surveillance systems can rule out false associations and identify rare but real …
http://www.bmj.com/content/347/bmj.f5631

Research
Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study
Lisen Arnheim-Dahlström, associate professor1, Björn Pasternak, postdoctoral fellow2, Henrik Svanström, statistician2, Pär Sparén, professor1, Anders Hviid, senior investigator2
http://www.bmj.com/content/347/bmj.f5906

Abstract
Objective
To assess the risk of serious adverse events after vaccination of adolescent girls with quadrivalent human papillomavirus (qHPV) vaccine.

Design
Register based cohort study.

Setting
Denmark and Sweden, October 2006 to December 2010.

Participants
997,585 girls aged 10-17, among whom 296,826 received a total of 696,420 qHPV vaccine doses.

Main outcome measures
Incident hospital diagnosed autoimmune, neurological, and venous thromboembolic events (53 different outcomes) up to 180 days after each qHPV vaccine dose. Only events with at least five vaccine exposed cases were considered for further assessment. Rate ratios adjusted for age, country, calendar year, and parental country of birth, education, and socioeconomic status were estimated, comparing vaccinated and unvaccinated person time. For outcomes where the rate ratio was significantly increased, we regarded three criteria as signal strengthening: analysis based on 20 or more vaccine exposed cases (reliability), rate ratio 3.0 or more (strength), and significantly increased rate ratio in country specific analyses (consistency). We additionally assessed clustering of events in time and estimated rate ratios for a risk period that started on day 181.

Results
Among the 53 outcomes, at least five vaccine exposed cases occurred in 29 and these were analysed further. Whereas the rate ratios for 20 of 23 autoimmune events were not significantly increased, exposure to qHPV vaccine was significantly associated with Behcet’s syndrome, Raynaud’s disease, and type 1 diabetes. Each of these three outcomes fulfilled only one of three predefined signal strengthening criteria. Furthermore, the pattern of distribution in time after vaccination was random for all three and the rate ratios for these outcomes in the period from day 181 after vaccination were similar to the rate ratios in the primary risk period. The rate ratios for five neurological events were not significantly increased and there were inverse associations with epilepsy (rate ratio 0.66, 95% confidence interval 0.54 to 0.80) and paralysis (0.56, 0.35 to 0.90). There was no association between exposure to qHPV vaccine and venous thromboembolism (0.86, 0.55 to 1.36).

Conclusions

This large cohort study found no evidence supporting associations between exposure to qHPV vaccine and autoimmune, neurological, and venous thromboembolic adverse events. Although associations for three autoimmune events were initially observed, on further assessment these were weak and not temporally related to vaccine exposure. Furthermore, the findings need to be interpreted considering the multiple outcomes assessments

Ethical Tradeoffs in Trial Design: Case Study of an HPV Vaccine Trial in HIV-Infected Adolescent Girls in Lower Income Settings

Developing World Bioethics
August 2013  Volume 13, Issue 2  Pages ii–iii, 57–104
http://onlinelibrary.wiley.com/doi/10.1111/dewb.2013.13.issue-2/issuetoc

Special Issue: Anti-retrovirals for treatment and prevention – new ethical challenges
[Six articles]

ARTICLE
Ethical Tradeoffs in Trial Design: Case Study of an HPV Vaccine Trial in HIV-Infected Adolescent Girls in Lower Income Settings
J.C. Lindsey, S.K. Shah, G.K. Siberry, P. Jean-Philippe, M.J. Levin
http://onlinelibrary.wiley.com/doi/10.1111/dewb.12028/abstract

Abstract
The Declaration of Helsinki and the Council of the International Organization of Medical Sciences provide guidance on standards of care and prevention in clinical trials. In the current and increasingly challenging research environment, the ethical status of a trial design depends not only on protection of participants, but also on social value, feasibility, and scientific validity. Using the example of a study assessing efficacy of a vaccine to prevent human papilloma virus in HIV-1 infected adolescent girls in low resource countries without access to the vaccine, we compare several trial designs which rank lower on some criteria and higher on others, giving rise to difficult trade-offs. This case demonstrates the need for developing more nuanced guidance documents to help researchers balance these often conflicting criteria.

Study of a measles outbreak in Granada with preventive measures applied by the courts, Spain, 2010 to 2011

Eurosurveillance
Volume 18, Issue 43, 24 October 2013
http://www.eurosurveillance.org/Public/Articles/Archives.aspx?PublicationId=11678

Surveillance and outbreak reports
Study of a measles outbreak in Granada with preventive measures applied by the courts, Spain, 2010 to 2011
by E Navarro, MM Mochón, MD Galicia, I Marín, J Laguna

Abstract
Measles had practically been eliminated in Granada since the systematic vaccination of children with two doses introduced in 1984. However, in 2009 the disease returned in the form of small outbreaks. This study describes the measles outbreak that occurred in Granada from October 2010 to August 2011 and the measures imposed to control it. Information was sourced from the records of the Andalusian epidemiological surveillance system. A total of 308 cases were recorded, representing an incidence rate of 33.6 cases per 100,000 inhabitants. The first wave of the epidemic took place in Granada city, with the majority of cases occurring among families who lived in the Albaycín neighbourhood and were opposed to vaccination for ideological and/or religious reasons. The initial cases were in unvaccinated children  aged 1 to13 years. The outbreak later spread throughout the province. To control the outbreak, the vaccination schedule for the exposed children was brought up to date. The Regional Ministry of Health decided to take legal action in order to ensure vaccination of those in the initial nucleus of the outbreak.

Editorial: Influenza Vaccination in 2013-2014 – Achieving 100% Participation

JAMA   
October 23/30, 2013, Vol 310, No. 16
http://jama.jamanetwork.com/issue.aspx

Editorial | October 23/30, 2013
Influenza Vaccination in 2013-2014 – Achieving 100% Participation
Kathleen M. Neuzil, MD, MPH1

Excerpt http://jama.jamanetwork.com/article.aspx?articleid=1758725
Every year, the public and health care system experience clinical and financial consequences of influenza epidemics. Influenza infection leads to hospitalizations, deaths, excess medication usage, and days missed from work and school. Influenza is a preventable disease, and advisory bodies in the United States recommend influenza vaccine for everyone 6 months and older, with particular emphasis on the need to vaccinate young children, older adults, and persons of all ages with high-risk conditions, including cardiovascular disease.1 In 2013, an unprecedented number of influenza vaccines are available in the US market, including quadrivalent vaccines, live, attenuated vaccines, high-dose vaccines, and vaccines manufactured in cell culture.1      Comparative trials in certain pediatric age groups have shown the relative benefits of live, attenuated influenza vaccine and as yet unlicensed adjuvanted vaccines.2,3 Likewise, studies evaluating the comparative benefits of high-dose vs standard-dose influenza vaccines in older adults are nearing completion.4

Association Between Influenza Vaccination and Cardiovascular Outcomes in High-Risk Patients

JAMA   
October 23/30, 2013, Vol 310, No. 16
http://jama.jamanetwork.com/issue.aspx

Original Investigation | October 23/30, 2013
Association Between Influenza Vaccination and Cardiovascular Outcomes in High-Risk PatientsA Meta-analysis
Jacob A. Udell, MD, MPH, FRCPC1; Rami Zawi, MD2; Deepak L. Bhatt, MD, MPH3,4; Maryam Keshtkar-Jahromi, MD, MPH5,6; Fiona Gaughran, MD7,8; Arintaya Phrommintikul, MD9; Andrzej Ciszewski, MD10; Hossein Vakili, MD11; Elaine B. Hoffman, PhD4; Michael E. Farkouh, MD, MSc, FRCPC12; Christopher P. Cannon, MD4

Abstract http://jama.jamanetwork.com/article.aspx?articleid=1758749
Importance.  Among nontraditional cardiovascular risk factors, recent influenza-like infection is associated with fatal and nonfatal atherothrombotic events.

Objectives.  To determine if influenza vaccination is associated with prevention of cardiovascular events.

Data Sources and Study Selection. A systematic review and meta-analysis of MEDLINE (1946-August 2013), EMBASE (1947-August 2013), and the Cochrane Library Central Register of Controlled Trials (inception-August 2013) for randomized clinical trials (RCTs) comparing influenza vaccine vs placebo or control in patients at high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safety events.

Data Extraction and Synthesis.   Two investigators extracted data independently on trial design, baseline characteristics, outcomes, and safety events from published manuscripts and unpublished supplemental data. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up.

Main Outcomes and Measures  Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derived for composite cardiovascular events, cardiovascular mortality, all-cause mortality, and individual cardiovascular events. Analyses were stratified by subgroups of patients with and without a history of acute coronary syndrome (ACS) within 1 year of randomization.

Results  Five published and 1 unpublished randomized clinical trials of 6735 patients (mean age, 67 years; 51.3% women; 36.2% with a cardiac history; mean follow-up time, 7.9 months) were included. Influenza vaccine was associated with a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P = .003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI, 0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Results were similar with the addition of unpublished data.

Conclusions and Relevance  In a meta-analysis of RCTs, the use of influenza vaccine was associated with a lower risk of major adverse cardiovascular events. The greatest treatment effect was seen among the highest-risk patients with more active coronary disease. A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular end points.