Vaccines and Global Health: The Week in Review 13 December 2014

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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David R. Curry, MS
Executive Director
Center for Vaccine Ethics and Policy
a program of the
– Division of Medical Ethics, NYU Medical School
– The Wistar Institute Vaccine Center
– Children’s Hospital of Philadelphia Vaccine Education Center
Associate Faculty, Division of Medical Ethics, NYU Medical School

POLIO [to 13 December 2014]

POLIO [to 13 December 2014]
Public Health Emergency of International Concern (PHEIC)

GPEI Update: Polio this week – As of 10 December 2014
Global Polio Eradication Initiative
[Editor’s Excerpt and text bolding]
Full report: http://www.polioeradication.org/Dataandmonitoring/Poliothisweek.aspx
:: This week, donors, partners and stakeholders of the GPEI convened at the Global Polio Partners Group (PPG) meeting in Geneva to discuss the current status of the global effort and priorities for 2015 and beyond. Discussions also focused on polio legacy planning, strengthening routine immunization, the status of IPV introduction into OPV-using countries, and preparations for the trivalent to bivalent oral polio vaccine switch.
:: In the north of Madagascar, supplementary immunization activities are planned for 15 – 19 December in response to the outbreak of circulating vaccine-derived poliovirus type 1. National Immunization Days are planned for 19 – 23 January. The aim is to boost immunity across the country against all strains of poliovirus using trivalent oral polio vaccine.
:: For the first time ever, only 1 case of wild poliovirus has been reported in Africa in the last 4 months. The case had onset of paralysis on 11 August in Somalia.

Selected country report content:
Afghanistan
:: One new wild poliovirus type 1 (WPV1) case was reported in the past week in Afghanistan, in Spin Boldak, a district bordering Balochistan, Pakistan, in Kandahar province, which had not previously reported a case in 2014. The most recent case had onset of paralysis on 5 November in Kandahar district. The total number of WPV1 cases for 2014 in Afghanistan is now 24 compared to 11 at this time last year.
:: Given the growing wild poliovirus type 1 outbreak in neighbouring Pakistan, Afghanistan continues to conduct supplementary immunization activities (SIAs) to limit the spread of imported polioviruses and to tackle residual endemic transmission. In addition to SIAs using oral polio vaccine (OPV) two special activities were conducted in mid-November using Inactivated Polio Vaccine (IPV) in several high risk districts of the Southern and the Eastern Regions. Subnational Immunization Days (SNIDs) are planned in high risk areas of the south and east using monovalent oral polio vaccine (OPV) on 21 – 23 December, and 11 – 13 January using bivalent OPV.
Nigeria
:: Over 4 months has passed since the last case of WPV1 was reported in Nigeria.
:: One new type 2 circulating vaccine-derived poliovirus (cVDPV2) case was reported from Ajingi district of Kano state in the past week, with onset of paralysis on 2 November. The total number of cVDPV2 cases for 2014 in Nigeria is now 28.
Pakistan
:: Eight new wild poliovirus type 1 (WPV1) cases were reported in the past week. One is from Balochistan province in Killa Abdullah district (across the border from Spin Boldak, Afghanistan); 6 are from the Federally Administered Tribal Areas (FATA) (4 from Khyber Agency, 1 from South Waziristan and 1 from Frontier Region Bannu); and 1 from Nowshera district, in Khyber Pakhtunkhwa (KP) province. The total number of WPV1 cases in Pakistan in 2014 is now 276, compared to 74 at this time last year. The most recent WPV1 case had onset of paralysis on 22 November, from Frontier Region Bannu, FATA.
:: Immunization activities are continuing with particular focus on known high-risk areas, in previously inaccessible areas of FATA. At exit and entry points of conflict-affected areas 100 permanent vaccination points are being used to reach internally displaced families as they move in and out of the inaccessible area. Over 1 million doses of vaccine have been used in the past few months to vaccinate people passing through transit points and in host communities, including over 850,000 children under 10 years old.
West Africa
:: The Ebola crisis in western Africa is impacting on the implementation or polio eradication activities in Liberia, Guinea and Sierra Leone. Supplementary immunization activities in these countries have been postponed and the quality of acute flaccid paralysis surveillance has markedly decreased this year.
:: Even as polio programme staff across West Africa support efforts to control the Ebola outbreak affecting the region, efforts are being made in those countries not affected by Ebola to vaccinate children against polio.

New York Times
http://www.nytimes.com/
Accessed 13 December 2014
Anti-Polio Worker Slain in Pakistan
By SALMAN MASOOD
DEC. 9, 2014
ISLAMABAD, Pakistan — A pair of unidentified gunmen killed a polio vaccinator in central Pakistan on Tuesday in yet another assault on workers who are part of a government effort to curb the disease.

Pakistan is struggling to contain the spread of polio as militant violence and a chaotic political environment hobble the campaign’s progress. At least 268 new cases of polio have been reported in the country this year.

Despite the government’s repeated vows to protect health workers, the attacks continue. Taliban militants have targeted workers across the country, accusing them of being spies for Western countries.

The latest shooting took place about 9 a.m. in Faisalabad, an industrial city in Punjab Province, on the second day of a three-day national vaccination campaign.

Two men on a motorbike opened fire on a health worker, Muhammad Sarfraz, in the Peoples Colony neighborhood, officials said. Mr. Sarfraz, 40, was a schoolteacher who had volunteered for the campaign.

“The attackers shot six bullets in his body and managed to escape,” said Ali Waseem, a senior police official. A female worker with Mr. Sarfraz was unharmed.

Officials suspended the campaign in Faisalabad district.

Jundullah, a Taliban splinter group, claimed responsibility. Ahmed Marwat, a Jundullah spokesman, was quoted by local news media as saying that anti-polio workers would be targeted throughout Pakistan.

But police officials in Faisalabad speculated that the attack could have been a result of personal enmity. Mr. Sarfraz had been attacked twice this year, the officials said.

Waqar Gillani contributed reporting from Lahore, Pakistan.

WHO: Ebola response roadmap – Situation report 10 December 2014

WHO: Ebola response roadmap – Situation report 10 December 2014
Summary [Excerpt]
A total of 17 942 confirmed, probable, and suspected cases of Ebola virus disease (EVD) have been reported in five affected countries (Guinea, Liberia, Mali, Sierra Leone, and the United States of America) and three previously affected countries (Nigeria, Senegal and Spain) up to the end of 7 December. There have been 6388 reported deaths. Reported case incidence is slightly increasing in Guinea (103 confirmed and probable cases reported in the week to 7 December), declining in Liberia (29 new confirmed cases in the 3 days to 3 December), and may still be increasing in Sierra Leone (397 new confirmed cases in the week to 7 December). The case fatality rate across the three most-affected countries in all reported cases with a recorded definitive outcome is 76%; in hospitalized patients the case fatality rate is 61%.

Response activities in the three intense-transmission countries continue to progress in line with the UNMEER aim to isolate and treat 100% of EVD cases and safely bury 100% of EVD-related deaths by 1 January. At a national level, there is now sufficient bed capacity in EVD treatment facilities to treat and isolate all reported EVD cases in each of the three intense-transmission countries, although the uneven distribution of beds and cases means there are serious shortfalls in some areas. Similarly, each country has sufficient and widespread capacity to bury all reported EVD-related deaths; however, because not all EVD-related deaths are reported, and many reported burials are of non-EVD-related deaths, it is possible that some areas still have insufficient burial capacity. Every district that has reported a case of EVD in the three intense-transmission countries has access to a laboratory within 24 hours from sample collection. All three countries report that more than 80% of registered contacts associated with known cases of EVD are being traced, although contact tracing is still a challenge in areas of intense transmission and in areas of community resistance. Rapidly increasing capacity for case finding and contact tracing in areas with low and moderate levels of transmission will be necessary to end local chains of transmission….

Gavi commits to purchasing Ebola vaccine for affected countries

Gavi commits to purchasing Ebola vaccine for affected countries
Vaccine Alliance ready to begin procurement as soon as WHO recommends a vaccine for use

Geneva, 11 December 2014 – Plans to purchase millions of doses of an Ebola vaccine to support large-scale vaccination efforts were today agreed by the board of Gavi, the Vaccine Alliance. Today’s decision means that Gavi will be ready to act as soon as a safe, effective vaccine is recommended for use by the World Health Organization.
The Gavi Board endorsed plans that could see up to US$ 300 million committed to procure the vaccines, to be used to immunise at risk populations in affected countries. Up to an additional US$ 90 million could be used to support countries to introduce the vaccines and to rebuild devastated health systems and restore immunisation services for all vaccines in Ebola-affected countries.

Join forces
To meet the funding requirements of the approved Ebola initiative, Gavi will use a combination of existing and new sources of funds and join forces with initiatives that have already pledged funding to address the Ebola crisis.
Although there is currently no approved Ebola vaccine, two manufacturers have candidates undergoing human trials, with more manufacturers due to begin human trials with their candidate vaccines shortly. The Gavi Board’s decision to support the preparations for procuring Ebola vaccines while still awaiting a WHO recommendation was taken in light of the seriousness of the situation and the risks associated with delays in making a vaccine available.

Critical importance
“The Ebola outbreak reminds us of the critical importance of vaccines in fighting infectious diseases,” said Gavi CEO Dr Seth Berkley. “The Board’s decision underlines Gavi’s commitment to support the people of the Ebola-affected countries by ensuring that they will have access to a WHO-recommended vaccine as soon as one is approved and available from manufacturers.”

Noting the seriousness of the epidemic and the devastating consequences for people and communities, the Gavi Board approved plans that could see:
:: Up to US$ 300 million spent procuring up to 12 million courses of WHO recommended Ebola vaccines
:: Up to US$ 45 million to help countries roll out the vaccine, including critical activities such as health worker training, social mobilisation, surveillance and, if required, improvements to cold storage facilities
:: Up to US$ 45 million to assist with the recovery of health systems and immunisation services for all vaccines in the countries affected by the outbreak
The Ebola outbreak, and its tragic effect on countries where we have been working for years, has tested Gavi’s ability to respond quickly to an urgent need and I am proud of the decision taken by the Board today.

Stockpiles
In addition to supporting the use of Ebola vaccines to control the current epidemic, Gavi funding could also be used to create stockpiles of first- and second-generation Ebola vaccines which countries can access rapidly in future outbreaks. Gavi already funds similar stockpiles for yellow fever, meningitis A and oral cholera vaccines.

“Gavi has a responsibility to those in need,” said Gavi Board Chair Dagfinn Høybråten. “The Ebola outbreak, and its tragic effect on countries where we have been working for years, has tested Gavi’s ability to respond quickly to an urgent need and I am proud of the decision taken by the Board today. We are making determined efforts to ensure that people living in Ebola-affected countries are protected as soon as possible and do not have to face another terrible outbreak in the future.”
Oversight
To maintain effective oversight of Gavi’s Ebola activities, the Board requested a schedule of regular updates through the Executive Committee and other governance mechanisms.

The Gavi Board’s decision was based on recommendations drawn up following three months of intensive collaboration between the Gavi Secretariat, Ebola-affected countries, the African Development Bank, WHO, UNICEF, the US Centers for Disease Control and Prevention, the World Bank, vaccine manufacturers, civil society organisations including Médecins Sans Frontières, and donors.

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WHO welcomes Gavi support for Ebola candidate vaccines
11 December 2014, Geneva – The World Health Organization (WHO) welcomes the commitment by Gavi, the Vaccine Alliance to support the procurement of vaccines as soon as WHO recommends one for use.

“This is yet another example of the rapid mobilization from partners and stakeholders to respond to the Ebola outbreak with innovative products. If the vaccines currently being tested live up to their promise of safety and efficacy, this will be the fastest vaccine development and roll-out in history”, said Dr Marie-Paule Kieny, WHO Assistant Director-General of Health Systems and Innovation.

WHO has been spearheading efforts to galvanize the research and development of vaccines that could be used to curb the outbreaks. Accelerated efforts are underway to evaluate a number of Ebola candidate vaccines with preliminary results anticipated in early 2015. Effective strategies for vaccination may be to prioritize those greatest at risk of contracting Ebola; for example, frontline workers and close contacts of people proven to be infected with the virus.

The Gavi announcement follows the high level meeting convened by WHO, the African Development Bank, the West African Health Organization and the World Bank on Building Resilient Health Systems in Ebola-affected countries in Geneva with the aim of laying the foundation for stronger health systems in the medium- to long-term.

[U.S.] Secretary Burwell issues declaration under PREP Act to support development of Ebola vaccines

[U.S.] Secretary Burwell issues declaration under PREP Act to support development of Ebola vaccines
Important step in effort to develop Ebola vaccines to combat current, future outbreaks
December 9, 2014
[Full text; Editor’s text bolding]
Health and Human Services Secretary Sylvia M. Burwell today announced a declaration under the Public Readiness and Emergency Preparedness (PREP) Act to facilitate the development and availability of experimental Ebola vaccines. This declaration is intended to assist in the global community’s effort to help combat the current epidemic in West Africa and help prevent future outbreaks there.

The declaration provides immunity under United States law against legal claims related to the manufacturing, testing, development, distribution, and administration of three vaccines for Ebola virus disease. It does not, generally, provide immunity for a claim brought in a court outside the United States.

For many years, the U.S. has encouraged vaccine development by managing liability and compensation, starting with the National Childhood Vaccine Injury Act of 1986. The PREP Act was designed to facilitate the development of medical countermeasures to respond to urgent public health needs, including the development of critical vaccines like those to prevent the spread of Ebola. This U.S. declaration under the PREP act is part of a global dialogue to address these issues in the U.S., and other countries where the vaccine is being developed, manufactured and potentially used.

“My strong hope in issuing this PREP Act declaration in the United States is that other nations will also enact appropriate liability protection and compensation legislation,” said Secretary Burwell. “As a global community, we must ensure that legitimate concerns about liability do not hold back the possibility of developing an Ebola vaccine, an essential strategy in our global response to the Ebola epidemic in West Africa.”

The PREP Act declaration is expected to strengthen the incentive to conduct research and spur development, manufacturing, and the potential use of the vaccines in large scale vaccination campaigns in West Africa. The PREP Act declaration provides legal protection under U.S. law for three vaccine candidates:
:: the GlaxoSmithKline’s Recombinant Replication Deficient Chimpanzee Adenovirus Type 3-Vectored Ebola Zaire Vaccine known as ChAd3-EBO-Z;
:: the BPSC1001 vaccine, known as rVSV-ZEBOV-GP, made by BioProtection Services Corporation, a subsidiary of Newlink Genetics; and
:: the Ad26.ZEBOV/MVA-BN-Filo vaccine manufactured by Janssen Corporation, subsidiary of Johnson & Johnson/Bavarian Nordic.
Similar PREP Act declarations have been issued, revised or renewed 14 times since the Act was signed in 2005. Past declarations have covered vaccines used in H5N1 pandemic influenza clinical trials in 2008, products related to the H1N1 influenza pandemic in 2009, and the development and manufacturing of antitoxins to treat botulism in 2008.

For more information about the PREP Act, visit http://www.phe.gov/preparedness/legal/prepact/pages/default.aspx.

Vaccinations with VSV-ZEBOV have been suspended and will resume in early 2015 [11 December 2014]

Vaccinations with VSV-ZEBOV have been suspended and will resume in early 2015
Press release by University Hospitals of Geneva (HUG)
Geneva, 11 December 2014
Since 10 November 2014, a total of 59 volunteers have been included in the clinical trial of the experimental VSV-ZEBOV Ebola vaccine at the University Hospitals of Geneva (HUG). All of these volunteers are in good health and are being monitored regularly by the team in charge of the study.

Initial results show that the vaccination is very well tolerated. In the hours and days following the injection, some volunteers had some fever or muscle pain; these reactions were expected and participants were informed about them during the medical consultation which took place before their inclusion in the study.

Close monitoring of the volunteers by the VSV-ZEBOV Geneva study team has allowed the identification of four cases of mild joint pain (in the hands and feet), 10 to 15 days after receiving the injection. These symptoms were not part of the expected side effects and were not included in the prior information given to volunteers, since this vaccine is being tested on humans for the first time.

As a precautionary measure, the study team has declared a pause in the injections. No injections will take place next week. This pause is beginning one week earlier than an already
scheduled pause in the vaccination series. The available time will serve to gather more information and exchange it with the other teams that are testing the same experimental vaccine. Several investigations have been launched to ensure that the symptoms which have been identified are benign and transient. In the context of clinical trials the safety of volunteers is always a priority.
The onset of joint pain after infection or vaccination is very common. This happens, for instance, in one out of five vaccinations against rubella. This is a well-documented phenomenon which does not worry specialists. However, it deserves to be carefully studied in order to update the information which is provided to the volunteers. The temporary interruption of a clinical trial is a standard precautionary measure in such cases.
The VSV-ZEBOV Geneva study team is constantly exchanging information with teams conducting similar studies in the United States, Canada, Germany and Gabon. Up to now, these teams have not observed inflammatory symptoms among their volunteers. In Geneva, vaccinations will resume on 5 January 2015, with maximum 15 volunteers per week in order to ensure optimal monitoring conditions.

Pdf: http://www.hug-ge.ch//sites/interhug/files/actualites/ebola/news_vaccin_ebola_11_12_2014.pdf

Dose regimen of favipiravir for Ebola virus disease

The Lancet Infectious Diseases
Online First
Correspondence
Dose regimen of favipiravir for Ebola virus disease
France Mentré, Anne-Marie Taburet, Jeremie Guedj, Xavier Anglaret, Sakoba Keïta,
Xavier de Lamballerie, Denis Malvy
Published Online: 27 November 2014
DOI: http://dx.doi.org/10.1016/S1473-3099(14)71047-3
Full Text
Although several antivirals have shown efficacy against Ebola virus infection in vitro or in animal models, none of them have been yet assessed in human beings with Ebola virus disease.

Potential drug candidates include favipiravir,1 a nucleotide analogue approved for novel or re-emerging influenza in Japan. This year, results of two independent studies in mice infected with Ebola virus showed that the initiation of 150 mg/kg favipiravir twice a day within 6 days of infection induced rapid virus clearance, reduced biochemical parameters of disease severity, and led to 100% survival.2, 3 Moreover, favipiravir had a good safety profile in thousands of patients worldwide, is immediately available, and can be used orally, leading the French drug safety agency (ANSM) to approve the compassionate use of favipiravir in patients with Ebola virus disease. Here we explain the approach we used to propose a dose regimen in a forthcoming trial in Guinea that is assessing survival in adults with Ebola virus disease who receive favipiravir.

First we used the dose regimen used to successfully treat mice to estimate target plasma favipiravir concentrations for human patients. Using data provided by the manufacturer, we showed that, in mice, 150 mg/kg every 12 h led to mean daily minimal concentrations (Cmin, 12 h post-dosing) of 5 μg/mL, average concentrations (Cave, defined by the area under the concentration curve from 0 h to 24 h divided by 24 h) of 58 μg/mL, a half-life of 1•8 h, and maximal concentrations (Cmax) of 200 μg/mL. Since 10% of favipiravir is bound to plasma proteins in mice, unbound average (Cave_u) was therefore targeted to 52 μg/mL, and minimum concentrations (Cmin_u) to 4•5 μg/mL. Of note, 52 μg/mL is higher than the 99% inhibitory concentration with Zaire ebolavirus Mayinga 1976 strain (estimated to be 29 μg/mL).3 Plasma protein binding in human beings was 54%; therefore, plasma Cmin and Cave were targeted to 10 μg/mL and 113 μg/mL, respectively.

Second, we used the pharmacokinetic model developed by the manufacturer in human beings with the parameter values estimated in US healthy volunteers to assess a dose regimen that could achieve these targeted concentrations. Simulations were done with various maintenance doses of 1000 mg, 1200 mg, and 1800 mg twice a day and led to median Cave at a steady state of 66•8 μg/mL (90% prediction interval 57•2–76•5), 83•3 μg/mL (72•2–95•3), and 134•4 μg/mL (115•9–152•0), respectively. Although the dose of 1200 mg twice a day gave a slightly lower Cave than targeted, it minimised the chance of relapse (Cmin of 57 μg/mL) and remained in the range of exposures previously assessed in human beings with good tolerance.

Since viral spread has to be blocked as soon and as strongly as possible after appearance of first symptoms, we assessed several loading dose strategies on day 1 to rapidly achieve high levels of exposure. In view of the short half-life of favipiravir, a dose of 2400 mg twice a day led to a low median Cmin of 4•3 μg/mL (90% prediction interval 0•6–15•6). Rather, concentrations achieved with a regimen of 2400 mg, 2400 mg, and 1200 mg every 8 h allowed us to achieve a Cmin at 8 h of 9•8 μg/mL (2•9–23•5) and a Cmin at 16 h of 45•2 μg/mL (12•9–85•1).

To summarise, we describe the method used to propose a relevant dose regimen of favipiravir to be assessed in patients with Ebola virus disease, in a context where trials are urgently needed. Our approach combined data on favipiravir efficacy against Ebola virus in vitro and in vivo with data provided by the manufacturer on favipiravir pharmacokinetics in uninfected mice and human beings. On the basis of these elements, we will assess favipiravir in adults with a loading dose of 2400 mg, 2400 mg, and 1200 mg every 8 h on day 1, and a maintenance dose of 1200 mg twice a day afterwards. Of note, this dose regimen is 50% greater than the one in the phase 3 trials of favipiravir for influenza in the USA (1800 mg twice a day on day 1, 800 mg twice a day on day 2–5). To reduce the chance of relapse in Ebola virus disease, we decided to give the treatment for 10 days, which corresponds to the time needed for an effective antibody response.4

Although modelling is a valuable method to optimise the search of a dosing regimen, it is not a substitute for clinical data. Tolerance, virological, and pharmacokinetic data will be obtained during the trial to help to refine the dose regimen.

We declare no competing interests. We thank Toyama Chemical for sharing with us detailed data on favipiravir pharmacokinetics. We also thank Caroline Semaille and Nathalie Morgensztejn from the French National Agency for the Safety of Medicine and Health Products for helpful discussions, and the REACTing network of Aviesan for scientific support.

References
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