The big test for malaria vaccine RTS,S

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In 2015, Africa accounted for 92% of global deaths and 90% of all malaria cases.

Beginning next year, the World Health Organisation will begin pilot tests of the injectable malaria vaccine RTS,S (or Mosquirix) on 750,000 children aged 5-17 months in Ghana, Kenya and Malawi. The vaccine has been successfully put through a Phase III trial, in which the drug is tested for safety and efficacy. Any decision on wider use will be taken based on the results of the pilot tests in the three countries. If the vaccine does indeed prove to be ready for large-scale use, it will be a milestone in the fight against malaria. Although the number of cases globally and in the African region came down by 21% between 2010 and 2015, in 2015 itself the number of deaths worldwide on account of the disease was as high as 429,000. According to WHO estimates, Africa accounted for 92% of these deaths, and 90% of the 212 million new cases that year. In such a scenario, even a vaccine with limited benefits could yield a substantial improvement. The vaccine, given in four doses, protects against Plasmodium falciparum, which is the most prevalent malaria parasite in Africa. The three countries have been chosen as they have settings with moderate-to-high transmission of malaria and already have in place malaria control programmes such as the use of bed-nets, rapid diagnostic tests and combination therapy. Each country is to decide where precisely to run the pilots.

The first three doses of the vaccine will be administered with a minimum interval of one month between each dose, followed by the fourth dose 15 to 18 months after the third dose. The first dose will be administered at about five months of age and the third dose has to be completed by nine months of age. While the drop-out rate increases as the number of doses increases, the biggest challenge is the fourth dose, which warrants a new immunisation contact to be made 15 to 18 months after the last dose. In Phase III trials, the efficacy of the vaccine was around 30% when children received all the four doses; the vaccine also reduced the most severe cases by a third. But there was a significant drop in these benefits when children did not receive the fourth dose. Given the low protection efficacy of the vaccine even in tightly controlled clinical settings, the pilot tests will be useful in evaluating the likelihood of replicating the immunisation schedule in the context of routine health-care settings. Also, the extent to which the vaccine reduces the all-cause mortality has to be evaluated as this was not “adequately addressed” during the trial. There is, specifically, a need to ascertain if excess cases of meningitis and cerebral malaria seen during the trials are causally related to the vaccination. Unlike other vaccines, the less-than-optimum protection offered by this vaccine would mean that existing malaria intervention measures will have to be used in conjunction to reduce the incidence of the disease.

Published in The Hindu on April 28, 2017

Zika vaccine Phase I trial to begin next month in India

measuring microcephaly. Photo WHO

The Phase I trial will not involve pregnant women.

Bharat Biotech International Ltd in Hyderabad will start a Phase I clinical trial of Zika virus vaccine (MR 766) in two centres in India next month. The inactivated  vaccine being tested in humans will be an African Zika virus strain. “We have already got the approval from DCGI [Drug Controller General of India] in March to carry out the Phase I clinical trial,” says Dr. Krishna Ella, Chairman and Managing Director of Bharat Biotech.

It will be a randomised, placebo-controlled, double-blind trial involving 48 adults, both men and women (who are not pregnant). Each volunteer will receive two doses of the vaccine on days 0 and 30 and followed-up for a year for both safety and immune responses. Three different dose ranges (2.5, 5 and 10 microgram) will be tested.

There will be three arms in the trial and each arm will get one of the three different dose ranges. There will be 16 subjects per arm.

The Phase I human clinical trial is being initiated based on the promising results seen in animals trials. In the animal trials, two doses of the vaccine made using an African Zika virus strain conferred 100% protection against mortality and disease in mice. The protection was the same when the mice were infected with an Asian and an African Zika virus strains.

While the viral load was “undetectable” in the case of vaccinated mice, the amount of virus in unvaccinated mice shot up four days after being infected. All the unvaccinated mice died eight days after infection by the African strain of the virus and 12 days after infection by the Asian strain.

Published in The Hindu on April 18, 2017

Bharat Biotech’s Zika virus vaccine confers 100% protection in mice

zika-microcephaly - Photo WHO

The vaccine made using an African strain confers 100% protection against infection and mortality caused by Asian and African Zika virus strains.

The Hyderabad-based Bharat Biotech’s killed (inactivated) Zika virus vaccine using an African strain (MR 766) has shown 100% efficacy against mortality and disease in animal studies. A ‘killed virus vaccine’ or ‘inactivated vaccine’ contains virus that has been grown in culture and then killed using physical or chemical processes. The whole virus was used for developing the vaccine.

Two doses (5 and 10 microgram) of the vaccine given through intramuscular route on days 0 and 21 to mice were found to protect the animals against Zika virus seven days after the second vaccination. The vaccine was found to confer 100% protection against infection caused by an Asian Zika virus strain as well as by the African Zika virus strain.

All the animals that were not vaccinated died eight days after infection by the African strain of the virus and 12 days after infection by the Asian strain. All the mice that did not receive the vaccine showed progressive morbidity before succumbing to infection.

While all the animals that received the vaccine exhibited “undetectable” viral load, the amount of virus present in animals that did not receive the vaccine peaked four days after being infected with either the African or Asian Zika virus strain. The results of the study were published in the journal Scientific Reports.

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The AG129 mouse is highly immunocompromised.

“The vaccine was developed using the African strain of the virus. It is important to prove that the vaccine developed with the African strain also protects against Zika infection caused by the contemporary Asian strains of Zika virus. Importing the contemporary Asian strains into the country was difficult, and hence the vaccine challenge studies with Asian strain had to be outsourced to a CRO in the U.S.,” says Dr. K. Sumathy from Bharat Biotech and the first author of the paper.

A particular kind of mouse — AG129 — which is highly immunocompromised and hence highly susceptible to virus infection was used for studying the protection conferred by the vaccine against Zika virus, disease pathogenesis and mortality. All the AG129 animals that received the vaccine showed 100% protection against the virus, demonstrating the superior efficacy of the vaccine.

Immunogenicity studied

Additionally, the level of immune response induced by the vaccine was also studied using another kind of mouse model — Balb/c mice. Unlike the AG129 mice, this mouse model is immunocompetent and elicits full spectrum of immune response. Animals that received the vaccine developed Zika neutralising antibodies on day 14 after the first dose and a week after the second dose. When the animals were infected with Zika virus post-vaccination, the virus in the vaccinated animals was “undetectable”, while 72-96 hours after infection it peaked in animals that did not receive the vaccine.

“In both the mice models, the vaccine-induced protective immunity against virus challenge was observed,” says Dr. Sumathy. “The vaccine was made only with the African virus strain, but the vaccinated mice was challenged [infected] with both the African and the Asian strains. Our vaccine offered equivalent protection against challenge with both the African and the Asian strains of Zika virus.”

Though 5 and 10 microgram of the vaccine were tested, the amount of antibodies elicited by the higher dose was “not significantly” higher than that elicited by 5 microgram of the vaccine, says Dr. Sumathy. Vaccination protected the animals against Zika virus and disease up to 14 and 20 days after being challenged with the virus.

Passive immunisation

Bharat Biotech also carried out passive immunization studies to show that the Zika vaccine-induced antibodies confer protection against the virus in mice that were exposed to the virus. Rabbits were vaccinated with the vaccine and the vaccine-induced antibodies were given to mice. While no virus was detected in mice 24-144 hours after passive immunisation, the viral load peaked 72-96 hours in mice that did not receive the vaccine-induced antibodies.

“Our study shows that the choice of Zika virus strain may not be a limiting factor in vaccine development,” she says.

Published in The Hindu on April 17, 2017

TB vaccine trial on adults begins in June in India

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The candidate vaccine VPM1002 will be tested in India.

In June this year, the Pune-based Serum Institute of India Pvt Limited will begin a Phase II/III vaccine trial for tuberculosis using a novel, recombinant BCG (bacillus Calmette-Guérin) vaccine. The double-blind, placebo-controlled, randomised trial will be carried out on 2,000 adults who have been successfully treated (and cured) for TB. While 1,000 adults will receive the vaccine, the remaining volunteers will receive a placebo. A single dose of the vaccine will be administered and the volunteers will be followed-up for a year. The trial will be conducted in 15-17 centres across India.

The new TB vaccine (VPM1002) that will be tested is based on the BCG vaccine that is currently being used but is more powerful and efficacious as it contains a gene that is better recognised by the immune system.

“Adults who have completed TB treatment will be first screened and enrolled if found eligible 2-4 weeks after completion of TB treatment,” says Dr. Prasad S. Kulkarni, Medical Director at Serum Institute. “Traces of the drugs may be present in the body for two weeks after completion of the treatment. Since the vaccine contains live, weakened bacteria, the drugs can kill them if given earlier than two weeks after completing the treatment.”

The vaccine will be first administered in 200 volunteers and safety of the vaccine will be tested. “If there are no safety concerns then the trial will continue in the remaining 1,800 volunteers,” he says.

The safety of the vaccine has already been tested in two Phase I trials — 80 adults in Germany (2009) and 24 adults in South Africa (2010) — and one Phase 2a trial in South Africa in 2012 in 48 newborn infants who have not been exposed to HIV. “These trials have confirmed the safety of the vaccine and sufficient strengthening of the immune system,” says Umesh Shaligram, Director-R&D, Serum Institute.

The results of the Phase 2a trial in newborns in South Africa published in February this year in the journal Clinical and Vaccine Immunology has confirmed the safety of the vaccine. “The VPM1002 is a safe, well-tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults,” the paper says.

BCG - WHO

The currently used BCG vaccine causes problems in HIV positive babies.

A Phase 2b trial on 416 newborns who have either been exposed or not exposed to HIV is currently under way in South Africa. “Results of the Phase 2b trial will be known in August-September this year. So far there have been no safety concerns,” Dr. Kulkarni says.

While the currently used BCG vaccine causes BCG-related disease in HIV-positive babies (due to reduced immunity), the recombinant version is expected to be safe in babies exposed to HIV.

Serum Institute is also planning to start next year a Phase III trial in newborns in India.

The recombinant vaccine was developed by a team led by Stefan H.E. Kaufmann, the founding director of the Max Planck Institute for Infection Biology, Berlin. The Max Planck Institute holds the patent and has licensed the vaccine to VPM; VPM, in turn, has out licensed it to Serum Institute.

In February last year Prof. Kaufmann told me: “The vaccine being tested is intended to replace the current BCG vaccine and will be administered to young children to protect them against tuberculosis. Adults may also be able to benefit from it later.”

Published in The Hindu on March 29, 2017

Can health spending of 2.5% of GDP only by 2025 help achieve the goals set by India’s National Health Policy?

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The National Health Policy wants to reduce infant mortality rate to 28 per 1,000 live births by 2019.

The long awaited National Health Policy announced a few days ago proposes to raise public health expenditure as a percentage of GDP from the current 1.15% to 2.5% by 2025. The resource allocation to individual States will be linked with their development indicators, absorptive capacity and financial indicators. “There will be higher weightage given to States with poor health indicators and they will receive more resources. The Policy aims to end inequity between States. But at the same time, States will be incentivised to increase public health expenditure,” says Manoj Jhalani, Joint Secretary — Policy, Ministry of Health and Family Welfare.

The catch

While public health expenditure as a percentage of GDP will reach 2.5% only by 2025, many of the goals listed in the Policy have a deadline of 2025 and some of them even earlier.

The Policy stresses on preventive healthcare by engaging with the private sector to offer healthcare services and drugs that are affordable by all. It wants to reduce out-of-pocket “catastrophic” health expenditure by households by 25% from current levels by 2025.

The focus is on providing free, comprehensive care in primary care for the most prevalent communicable and non-communicable diseases, and increased affordability of care at secondary and tertiary care services by a combination of public and not-for-profit private providers wherever necessary. It wants to increase the utilisation of public health facilities by 50% from the current levels by 2025.

Health card roll out

The Centre is working on introducing a health card — an electronic health record of individuals. “The health card will be for retrieving and sharing health data by lower [PHC] and higher [secondary and tertiary] healthcare facilities. It will be helpful when patients move from primary to secondary or tertiary healthcare facilities,” says Mr. Jhalani. “It will be launched in six months to one year’s time. It will be launched in those States that show interest to roll it out in certain districts or across the State.”

Disease control and elimination

Like the Health Ministry’s National strategic plan for tuberculosis elimination 2017-2025 report, the Policy wants to reduce incidence of new TB cases to reach elimination by 2025. In a similar vein, the policy has set 2017 as the deadline to eliminate kala-azar and lymphatic filariasis in endemic pockets, and 2018 in the case of leprosy. In the case of chronic diseases such as diabetes, cancer, cardiovascular diseases, it envisages a 25% reduction in premature mortality by 2025.

The Policy “aspires” to provide secondary care right at the district level and reduce the number of patients reaching tertiary hospitals. For the first time, there is any mention of public hospitals and facilities being periodically measured and certified for quality.

Pipe dream

The Policy has sharpened its war on tobacco by indicating a 15% relative reduction in tobacco use prevalence by 2020 and 30% by 2025. But the most ambitious target is providing access to safe water and sanitation by all by 2020. As per January 2016 Ministry of Drinking Water and Sanitation country paper, sanitation coverage was only 48%.

Reducing IMR and MMR

Other challenging targets set by the Policy include reducing infant mortality rate to 28 per 1,000 live births by 2019 and under five mortality to 23 per 1,000 live births by 2025. According to the National family Health Survey 4, IMR was 41 in 2015-16; it took 10 years to reduce IMR from 57 to 41. Similarly, under five mortality was 50 in 2015-16 and it took 10 years to reduce it from 74. Over 38% children under five years were stunted according to the NFHS-4 report. The Health Policy wants to reduce this by 40% by 2025.

Increasing immunisation coverage

As against 62% children 12-23 months old who were fully immunised in 2015-16 according to the NFHS-4 data, the Policy has set a target of 90% by 2025. “Going up to 70% coverage is hugely a challenge of reaching the community. But beyond 70% coverage, other factors come in and it becomes a very big challenge,” says Dr. Pradeep Haldar, Deputy Commissioner — Immunisation, Ministry of Health. According to J.P. Nadda, the Union Health Minister, the Mission Indradhanush has increased the annual increase in full immunisation from 1% to 5-7%.

Published in The Hindu on March 19, 2017

WHO’s website for vaccine safety information gains traction

MR vaccinationThe extent to which rumours about the safety of vaccines can impact the number of children vaccinated was witnessed in Tamil Nadu during the measles-rubella vaccination drive last month. Only about 50% of 17.6 million children between nine months and 15 years age in the State were vaccinated at the end of the campaign period on February 28. The campaign had to be extended for 15 days to cover over 95% of the target population. Though the slip in vaccination coverage due to rumour is unprecedented for the State, patently wrong, misleading, unbalanced information about vaccine safety has been a menace across the world for many years now.

While Andrew Wakefield’s 1998 infamous paper in The Lancet on measles, mumps, and rubella (MMR) vaccine that sparked the fear of vaccine-induced autism in children was retracted in 2010 and several studies have shown the safety of the vaccine, misapprehension and doubts about the vaccine safety still persists. Measles outbreaks in the UK in 2008 and 2009 and small measles outbreaks in the U.S and Canada have been attributed to the nonvaccination of children as a result of unfounded fear.

As is the norm today, parents and care givers often turn to Internet for information about vaccine safety. Chances are that many people inadvertently land on websites that contain wrong and alarmingly wrong, misleading information about vaccines and their safety. With such websites mushrooming on a daily basis, the World Health Organisation had launched the Vaccine Safety Net to provide doctors, parents and others access to “accurate and trustworthy information about vaccines”.

What is Vaccine Safety Net?

Launched in 2003, the Vaccine Safety Net is a global network of vaccine safety websites, evaluated by the WHO. Currently, the network has 47 member websites in 12 languages. According to the WHO, more than 173 million users every month access VSN websites. Websites are subjected to severe vetting by the Vaccine Safety Net before become approved to become a member. For instance, websites are required to contain correct, unbiased information about vaccine safety and have no links with the industry to become a member.

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The MR combination vaccine.

According to the WHO, efforts are on to include social media channels as well. “The network is currently piloting the process for reviewing Facebook pages to help get trustworthy vaccine safety messages to more diverse audiences,” WHO says.

The Indian Academy of Pediatrics’ Advisory Committee on Vaccines and Immunisation Practices (ACVIP) is one of the members of the network. “We became a member in August 2016,” says Dr. Vipin Vashishtha who is the webmaster of the site. “In the month of February alone there have been nearly 2,35,000 visits to the ACVIP website.”

How useful is the information?

At a time when President Donald Trump has raised the bogey of vaccine-induced autism through several tweets, the Institute for Vaccine Safety, Johns Hopkins Bloomberg School of Public Health, which is a member of network, has posted an article last month explaining why vaccines do not cause autism. One of Trump’s tweets reads: “Healthy young child goes to doctor, gets pumped with massive shot of many vaccines, doesn’t feel good and changes — Autish. Many such cases!” To a concerned parent that many vaccines given together as a combination vaccine, as in the case of MMR, is the cause of autism and other safety issues, the Centres for Disease Control and Prevention (CDC), a member of the network, in an explainer says: “Scientific data show that getting several vaccines at the same time does not cause any chronic health problems.”

In January this year, the ACVIP had sent out a letter to its nearly 24,000 members (who are paediatricians) and also posted it on the website explaining the basics of the measles-rubella vaccine campaign. Unfortunately, no information was made available on the website to counter the rumours about the MR vaccine. “We are in the process of uploading video messages to the website about the MR combination vaccine and its safety,” says Dr. Vashishtha.

Published in The Hindu on March 12, 2017

Low measles-rubella vaccination coverage may cause more cases of congenital rubella syndrome

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There is a great need to increase measles-rubella combination vaccine coverage in Tamil Nadu.

Only about 50 per cent of children aged nine months to 15 years in Tamil Nadu have been vaccinated by the measles-rubella combination vaccine since the campaign was launched. Unless and otherwise the vaccination coverage is increased to over 90%, there is a high possibility that the State would witness more rubella infections among older age groups. This would, in turn, lead to an increase in the number of newborns with congenital rubella syndrome (CRS) — hearing impairments, eye and heart defects and brain damage –  miscarriage and even infant deaths when  women get infected with rubella virus during the early stage of pregnancy.

Paradoxical increase in CRS

“When the rubella childhood immunisation coverage in communities is sub-optimal, there will more number of CRS cases than before as the infection shifts to an older age group. This is called the paradoxical increase in CRS,” says Dr. Jacob John who is co-chairman of the India Expert Advisory Group for measles and rubella. “There will be fewer CRS cases initially (one-three years) after immunisation. But in four-five years, as the infection shifts to an older age group, there will be more CRS cases than before.”

“In order to avoid this we need high coverage during both the campaign and the universal immunisation programme (UIP),” he says. There is a compulsion that the UIP becomes more efficient than before. “The national average for immunisation coverage is 72%. The country and the States have been stagnating. It’s a tall order that all States achieve above 95% coverage. This is an unprecedented requirement for UIP,” says Dr. John.

“The measles-rubella vaccination coverage in Goa is over 90%. In the case of Karnataka it is 87-88%. Tamil Nadu is struggling at 50%,” says Dr. Pradeep Haldar, Deputy Commissioner — Immunisation, Ministry of Health and Family Welfare, Government of India. “Karnataka has been able to handle the crisis of misinformation about the safety of the combination vaccine by adopting several strategies, while Tamil Nadu has been struggling.” As a result, the duration of the campaign in Tamil Nadu was extended by 15 days to cover more children in the nine months to 15 years age group.

“Of the 35 million children targeted in the five States [Karnataka, Tamil Nadu, Puducherry, Goa and Lakshadweep] we have already vaccinated 23 million children. If there were any concerns about vaccine safety we would have already seen it by now. But we have not seen any. So the vaccine is safe and the fear is unfounded,” stresses Dr. Haldar.

Problem with low coverage

Greece and Brazil witnessed the paradoxical increase in CRS due to shift of age distribution of rubella cases. In 1993, a “major rubella epidemic took place [in Greece] affecting women of child-bearing age at a rate higher than in previous years,” says a 1999 paper in the BMJ. Following the rubella epidemic, Greece saw the largest number of babies born with CRS.

In Greece, during the later 1970s and the 1980s, rubella vaccination coverage remained “consistently” below 50% and did not reach 50-60% before 1990. As a result, the proportion of pregnant women susceptible to rubella showed a steady increase — from 12% in 1971-75 to 24% in 1984-89 to 36% in 1990-91.“In 1993, the mean age of patients with rubella was 17 years and 64% were 15 years or older,” says the paper.

Published in The Hindu on March 4, 2017