The 14 December 2012 marked the end of a year long pentavalent vaccine study in Kerala, India. Kerala is a small state in the south with some of the best healthcare indicators in the country. The pentavalent vaccine is to replace the diphtheria, pertussis, and tetanus (DPT) vaccine and combines H influenza B and Hepatitis B with the older trivalent vaccine.

The pentavalent vaccine study in neighboring Tamil Nadu has about a month more to run. The final results may take another three months to be collated and analysed, but data on the first six months in Kerala are now available under the local right to information laws. The results are of interest not only to India, but also to the Asian countries, where the introduction of the vaccine has been controversial.

The controversy surrounding the vaccine relates to the fact that when introduced in neighbouring countries Sri Lanka, Bhutan, and Pakistan there were numerous “isolated instances” of unexplained or “sudden death” following vaccination. The deaths in Bhutan were said to be unrelated to vaccine, but probably related to viral encephalitis; the evidence provided for this was that the vaccine had not increased the death rate from viral encephalitis, when deaths following vaccination were added to the encephalitis deaths. However, after the vaccine was suspended in Bhutan there were “no further deaths from the encephalitis” in children under one year of age.

The WHO report on adverse events following immunisation in Sri Lanka found no alternate cause for deaths that would fall in the category “probably related” to vaccine under the Brighton Classification. The category “probably related” was removed, and the report stated that the deaths were unrelated to the vaccine.

The deaths in Pakistan were declared as “sudden infant death.” While these deaths were indeed sudden, it certainly is not SIDS, which refers only to unexplained death.

In view of these reports the National Technical Advisory on Immunization (NTAGI) in India suggested that the pentavalent vaccine be introduced only in two states and the harms and benefits evaluated after a year before it is considered for further rollout in the country.

A statistician friend analysed the deaths in Kerala against background mortality in the State. In the first six months of the immunisation programme 40,000 children were vaccinated with the new vaccine. Five of them died soon afterwards (in the next 36 hours or so). Four of the five occurred after the first dose of the vaccine and one after the second dose. Infant mortality in the state is 13 per 1000, and neonatal mortality is 7 per 1000. Post neonatal infant mortality of 6 per 1000 during 337 days (365-28 days of neonatal period) is 0.0178 per day per 1000 children. Using the Poisson probability theory my friend tells me that an observation of four deaths among the vaccinated 40000 vaccinated for the first time is highly inconsistent with the background mortality.

If five children were to die for every 40,000 vaccinated it means we can anticipate 3125 deaths after vaccination in India’s birth cohort of 25 million a year. A meticulously done population based study of Hib meningitis in India has shown that the incidence of haemophilus influenzae type b meningitis is 7/100,000 children under 5. This suggests there are 1750 cases of haemophilus influenzae type b meningitis in the nationwide birth cohort of 25 million. Given the estimated mortality rate 10% there would be 175 deaths from haemophilus influenzae type b meningitis in this cohort.  The vaccine related deaths appear to be far higher than the deaths likely to be prevented from meningitis.

The government standard operating procedure for AEFI recommends that all serious adverse events including seizures and hypotonic pathology be recorded. It states that approximately 570 cases of seizure, 570 cases of HHE and 20 cases of encephalopathy per 1 million doses of the DPT. The fact that none of these have been recorded after 40,000 children were immunised is suggestive that the recordings of adverse events are inadequate.

Two AEFIs related in time, place and/or by vaccine is considered a cluster.  When similar reactions occur with the same vaccine, across different countries, and with vaccines from a variety of manufacturers, it is difficult to consider them mere coincidences.  It will be interesting to see how the final arguments pan out in this debate.

Jacob Puliyel is a pediatrician and head of department at St Stephen’s Hospital in Delhi.