Letters to the Editor

Indian Pediatrics 2002; 39:1068-1071

Reply

We would like to thank Drs. Beri and Ojha for pointing out the oxymoron in the article. In the original manuscript we had used the abbreviation DTP for vaccine containing whole cell pertussis antigen, specifying that the formulation contained acellular antigen in one relevant place. On the suggestion from one reviewer, we changed the abbreviation to DTwP using the search and replace function on the Word program and failed to realize that this was inappropriate in the one particular sentence. Nevertheless, the point that we were trying to make was that when any two vaccines are combined, the combination has to be evaluated for safety and immunogenicity even though the individual components are themselves safe and immunogenic. We used the example of the combination of Hib and DTaP, which showed lower antibody levels to the Hib component when used in combination, to illustrate the need to do this. However, the requirement holds true for DTaP as well as DTwP. We would also like to point out that the USFDA did not find that TriHIBit "did not protect against Hib". The reason for their refusal to license the combination was that it produced lower antibody levels, which does not necessarily translate to lower efficacy. This combination is approved by the USFDA for the booster dose at 18 months and is licensed for use in several countries other than the United States.

We agree with the view of Drs. Beri and Ojha that based on available data, Hib vaccine cannot be recommended for routine use in the EPI in India. In the paper we have not attempted to make a case for this recommendation. This is because the burden of Hib disease in India and in other parts of Asia is not well established. The hospital-based data, including those from the IBIS study that is referred to in the letter, showed evidence that Hib disease occurs in India, that it is a common cause of meningitis and that most of the disease occurs in infancy but it does not provide information of the community incidence of disease. The complete results on Hib from the IBIS study were published recently(1). While it is true that the number of isolates (125 from 5798 patients) is low, it must be kept in mind that these results are from cultures from a variety of clinical syndromes and from age groups 1 month to 60 years. Most of the cases of invasive Hib disease were in children under 2 years with meningitis. If analysis is restricted to this age group and syndrome, the rates are not quite as low as suggested in the letter. In fact, the IBIS paper concludes by saying that Hib infection is a prominent preventable cause of death and hospitalization in children in India and that consideration should be given to use of Hib vaccination. Failure to use appropriate culture media is one reason for the low rates of Hib, but there are several others. These include high rates of prior antibiotic use, failure to perform lumbar punctures in all children with possible meningitis, improper handling, transport and storage of specimens prior to culture and death before presentation to a hospital with adequate laboratory facilities. In a recent community based study on Hib disease, we were able to document for evidence for most of the above (unpublished data, manuscript in preparation). Moreover, most studies on Hib incidence underestimate the burden of Hib pneumonia, which is believed to cause 4 times as many deaths as Hib meningitis in developing countries but is difficult to diagnose using conventional laboratory techniques. Thus, though we concur that one cannot make a case for routine Hib vaccination, it is due to a lack of good data on the burden of Hib disease rather than conclusive evidence that the burden does not justify the use of vaccination. The burden of Hib disease, or the lack of it, in India has been recently reviewed in an editorial in Indian Pediatrics(2). This article provides suggestions for further studies to establish the Hib disease burden in the country. We would encourage investigators in India to take up the challenge to establish the need for vaccination.

Drs. Beri and Ojha’ s comment that Indian children develop natural antibody to Hib is true for children everywhere. To deduce that this negates the need for Hib vaccination exposes their poor understanding of Hib epidemiology. In the pre-immunization era almost all children worldwide were exposed to and developed natural immunity by 5 years of age. The same was the case with poliovirus. Exposure occurs earlier in most developing countries. As a result most Hib disease occurs in infancy and immunity develops early; in India evidence for this is provided by the IBIS data. Early disease also occurs in Africa where the incidence of Hib disease is may fold higher than in Europe or North America. Hib vaccination is now routinely used in many African countries. Early exposure to Hib also carries a higher risk for the development of Hib meningitis, the most damaging outcome of invasive Hib disease. Withholding vaccination while waiting for naturally acquired infection, with an associated risk of invasive disease, to induce immunity shows a total lack of understanding about the concept of immunization.

Having agreed that there is lack of evidence for promoting Hib vaccine in routine infant immunization in India, we would like to point out that there is a difference between recommendations for vaccination as a public health tool at the country level and for use in individual children. The data from IBIS and other hospital-based data show that Hib disease occurs in children in India and that it is associated with high mortality. The vaccine has proven very high efficacy and an excellent safety profile. Under the circumstances, it would be unethical to deny the vaccine for children who can easily afford it, though it may not be a cost effective public health measure on a countrywide basis. As pediatricians who have first hand experience of the devastation Hib meningitis can cause, we have no hesitation in using it for our own children as well as recommending it to children under our care who can afford the vaccine. Our paper was aimed at facilitating the use of the vaccine in combination with DTP in this category of infants and not to promote its use in EPI in India.

It is very unfortunate that Drs. Beri and Ojha have such a cynical attitude towards research that involves participation of industry. However, this attitude is neither unusual nor unexpected and reflects current popular opinion. It also reflects their lack of involvement in clinical evaluation of new .vaccines or combinations and unfamiliarity with the processes. Almost all clinical evaluation of vaccines is carried out in collaboration with the manufacturers. Manufacturers are liable for the safety of their product and it is hard for them not to be involved in some way in research that is carried out using one of their products, especially one that is unlicensed. Preparation of pilot lots of vaccine for clinical evaluation using strict GMP procedures is often only possible through the manufacturers. In fact, it is in the interest of the public sector that academic investigators with established scientific integrity be involved in the research to ensure that it is conducted in an unbiased manner. All such studies are carried out with high scientific rigor, monitored by independent data and safety monitoring boards, institutional ethical committees and the regulatory agencies. All trial information is available for audit for 15-20 years after completion of the study. This was done in this study as well. All data were independently maintained and analyzed by the principal investigators as well as the manufacturer. It is unfair of Drs. Ojha and Beri to cast aspersions on the scientific integrity of members of the Academy without justification. We find the closing statement of the letter suggesting that the manufacturer in some way influenced the results of this study to be most objectionable.

While Drs. Ojha and Beri referred to SCF report in the BMJ they do not make any mention of the rebuttals that followed from UNICEF and other international agencies. The London School of Tropical Medicine and Hygiene, which sponsored that study, dissociated itself from the press statements issued by SCF, which many believed were a biased view and did not present the entire picture. While it is true that some manufacturers may have indulged in unethical conduct of trials, this is not common practice. In recent years, the public sector has played a very active role in ensuring the vaccines that do not have market in the industrialized countries but are important to developing countries are developed and evaluated. The public sector is increasingly playing a role to ensure that appropriate formulations of vaccines are developed and tested in countries with the largest burden, e.g. rotavirus and pneumococcal conjugate vaccines. These programs are only possible through active collaboration between the public and private sector and are essential for ensuring equity in the access to vaccines. Hence, rather than being overly critical of collaboration between public and private sector, we would like to suggest that the Academy and its members contribute to it for the benefit of children in India.

References

1. Invasive Bacterial Infections Surveillance (IBIS) Group of the International Clinical Epidemiology Network. Are Haemohilus influenzae infections a significant problem in India? A prospective study and review. Clin Infec Dis 2002; 34: 949-957.

2. Levine OS, Wenger J. Defining the burden of Hib disease in India. Indian Pediatr 2002; 39: 5-11.