Introducing Pentavalent Vaccine in India: How Public Interest Litigation Forced a Re-evaluation of the Evidence ENGLISH VERSION of article published in Turkish language

Turkish Medical Association's journal Turkish Medical Association's journal ISSN 1300-4387 Community and Physician 2012 Volume 27 (1) Page 75-80

Puliyel Jacob

Introducing Pentavalent Vaccine in India:
How Public Interest Litigation Forced a Re-evaluation of the Evidence

The Istanbul Experience – Natural Immunity
In the year 2000 researchers from Turkey contradicted conventional wisdom about Haemophilus influenzae type b (Hib) infection when they suggested that infants in Istanbul had high concentrations of maternally transferred anti-polyribosylribitol phosphate antibodies (anti-PRP) and they acquired natural active immunity at an early age. Tastan and colleagues investigated naturally acquired anti-PRP in healthy children during the first year of life in a prospective longitudinal study repeatedly testing anti-Hib titres in a cohort of 64 to arrive at this conclusion. Prior to this, it was said that children under 2 years have poor immune response to capsular polysaccharide of Hib and that under 18 months, even children who develop invasive Hib infections such as meningitis, do not develop a substantial concentration of serum antibodies.
In India, studies looking at antibody response to Hib vaccination showed that the babies had protective levels of antibodies even before vaccination was started. This was seen even at ages where passively acquitted immunity should have waned Also it was noted that post vaccination antibody titers raised some 10 fold higher in these children , than they did in the West.

The incidence of Hib diseases is 6 per 100,000 in Asia compared to 109 per 100,000 in the Western Pacific and Oceanic countries An editorial in the Bulletin of the WHO also highlights this difference. The longitudinal study from Turkey provided insights into why the incidence of invasive disease with Hib is low in Asia and also why post-vaccination titers were so high here. In Asians the vaccine was acting like a booster immunization dose, in children who were already immune.

Natural Immunity: Mechanisms
The author and colleagues tried to find reasons for this difference in immune response in the different regions and it led them to studies from the early 1970s showing that many bacteria having cross-reactive antigens to the Hib capsular polysaccharide. Bradshaw et al. demonstrated the development of serologically specific precipitate antibodies to Hib, after immunisation of the animals (burros) with Staphylococcus aureus and Bacillus subtillis. They demonstrated that strains of Staplylcocci, Group D Streptococci, Diphtheroids and Escherichia colil have cross-reactive antigens to Hib. Robbins et al. studied infants and noticed enhanced immune response to H. influenzae capsular polysaccharide when they have concurrent crossreacting E. coli infection of the gut. Such infants had a rapid and sustained rise in antibody to Hib. E. coli infection is common in developing countries like India and this may explain why infants in such countries developed antibodies and natural immunity to Hib

Research to Promote Vaccines
Many studies have been done to provide evidence of the need to introduce Hib in India but they failed to yield suitable data. The best and perhaps the most expensive such study, done over 2 years by Minz and colleagues found a Hib meningitis incidence of only 7.1/100,000 children under 5. In India’s population of 125 million children under 5, there would be about 8750 cases of Hib meningitis.
As these studies did not provide evidence of disease burden sufficient to warrant inclusion of immunization ‘Probe studies’ were introduced. Hib vaccine has been used as a ‘probe’ to evaluate the vaccine-preventable disease burden. According to Santosham, vaccine probe studies are randomized clinical trials of Hib vaccine in which non-specific endpoints such as purulent meningitis and radiographically confirmed pneumonia are used. The difference in the incidence of disease between vaccinated and unvaccinated children represents the vaccine-preventable disease burden. Probe studies were initiated in India also. However the probe study in Indonesia found more pneumonia (although not statistically significant) in the group vaccinated. The trial in Bangladesh found no significant reduction in either meningitis or pneumonia in those vaccinated with 3 doses of vaccine. We have published in the Indian Journal of Medical Research and the BMJ how a misleading press release suggesting benefits from the vaccine during the trial was released by WHO, GAVI and Johns Hopkins and others.
WHO Changes Its Position on Evidence
By happy coincidence, around this time the WHO changed its position on the need for evidence before including Hib in the routine immunization programmes of countries. The 1998 position paper states that countries should consider Hib burden before introducing the vaccine. The 2006 modification, instead recommends the inclusion of Hib vaccine in all routine immunization programs, regardless of national burden.
According to information obtained under India’s Right to Information after the Bangladesh study (June 2000 to Sept 2003) showed the vaccine was not useful, the Accelerated Development and Introduction Plans (ADIP) of GAVI stopped further funding of the probe study in India (November 2006) quoting the changed WHO position paper.
However by the time the Indian probe study was stopped, data from the first part of the study on incidence and mortality from pneumonia and meningitis had already been collected. Mortality in the three centers for meningitis ranged between 0 to 4.7%. Projecting this mortality data on the figures for meningitis obtained from the Minz study, one would expect 440 deaths among the 8750 cases of meningitis all over India. The vaccination of this population with Pentavalent vaccine (DPT + Hib + Hepatitis B) being recommended by the WHO ($10 for 3 doses/child) would cost $ 1250 million for vaccine alone. Without adding costs of administering the vaccine, if the vaccine is 100% efficacious, it would mean the cost is $3 million per life saved - in a country where per capita income is $1000
The DPT vaccine costs less than $0.30 per child. India at present manages to give this inexpensive DPT vaccine to only 50% of the population. This was to be replaced by a Pentavalent vaccine that costs $10 per child. In a desperate move to push the vaccine in India, GAVI has offered the vaccine free of charge for 3 years something it has not done before – not even in the poorest of poor countries in Africa.
Death by Vaccine
The cost is just one aspect of the problem. The other alarming aspect is deaths due to the Pentavalent vaccine. Deaths have been reported from Sri Lanka, Bhutan and Pakistan. These were investigated by expert committees and ‘no alternate cause of death’ was found. Using the Brighton Classification of adverse events following immunization (AEFI) this meant the vaccine was probably responsible for these deaths. However the expert committee looking into the deaths, removed the categories ‘probably related’ and ‘possibly related’ from the Brighton Classification, and reported the deaths were unrelated to vaccine.
Public Interest Lawsuit (PIL) in the Delhi High Court
A group of persons led by Professor K B Sexana (former Health Secretary to the Union of India) and including this author, filed a public interest lawsuit (PIL) in the Delhi High Court asking for the recommendation to introduce the Pentavalent vaccine be reconsidered given the high costs, low utility and risk of deaths. The Government of India then set up an ‘experts group’ to look into the matter and it was brought before a reconstituted National Technical Advisory Group on Immunization (NTAGI). The author was inducted into this NTAGI. The NTAGI suggested that the vaccine be introduced in only 2 states (Kerala and Tamil Nadu) to look for side effects and benefits if any. The programme was initiated in the two states around the 3rd week of December 2011.
Pentavalent Deaths in Kerala and PIL in the Kerala High Court
On the first day of starting the programme in Kerala one 2 month old baby died following immunization. The post mortem report suggested death was due to a hypersensitivity reaction. The Human Rights Legal Network (HRLN) filed an affidavit in the Kerala High Court on behalf of the mother of this girl who died, asking for the programme to be stopped. The Kerala High Court ordered the Government to submit its report. In its counter-affidavit the Government admitted that 4 children died from adverse events following immunization (AEFI) with the new vaccine within about a month of its introduction. No other clear ‘alternate cause’ of death was found as defined by WHO Brighton classification. One of the babies was under weight and the other had a heart murmur but the Government affidavit does not say these were considered the cause of the children’s death.

At the time of writing the courts are yet to give their verdicts. Judicial oversight however has already had a salutary and moderating influence on the NTAGI and the Government, as it has had to look for evidence to justify the decisions made.

The purpose of the PIL endeavor has not been to thwart an immunization programme. The petitioners insist that they are pro-science, actively pro-vaccine and want to see the practice of ethical and evidence-based-medicine. The exercise has been undertaken to bring in an evidence-based-vaccine policy that mandates universally available free vaccines when they are cost effective and retards the entry of harmful vaccines and those being introduced purely for private profits. The Right to Information Act of 2005 in India and an independent judiciary have been useful in demanding accountability from government and asking for the evidence-of-efficacy from entities that are looking for easy profits and a share in the huge India market.

Jacob Puliyel
St Stephens Hospital
Puliyel is member of the National Technical Advisory Group on Immunization of the Government of India