Pentavalent vaccine: Editorial from IJMR

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Vijay

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India-Drug : Pentavalent vaccine in India

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Copied for fair use

Gopal Dabade

http://icmr.nic.in/ijmr/2010/july/editorial1.pdf

Indian J Med Res 132, July 2010, pp 1-3

Editorial

Introducing pentavalent vaccine in the EPI in India: A counsel for caution

Indian J Med Res 132, July 2010, pp 1-3

The story of how pharmaceutical companies influenced scientists and official

agencies like the World Health Organization (WHO) in the recent swine flu scare1

and the saga of the undeclared conflicts of interests of members of the WHO's

Strategic Advisory Group of Experts2 has set off alarm bells around the world.

When trusted advisors are less than honest, the potential for harm is great, and

the feeling of betrayal is poignant.

A similar feeling of sadness and betrayal was evoked by the report of National

Technical Advisory Group on Immunization (NTAGI) sub-committee on Haemophilus

influenzae B (Hib) published recently3. On December 14, 2009, the Health

Secretary chaired a meeting to discuss the policy framework for vaccine

preventable disease in the country. Invited to this meeting were the

chairperson, vice-chairperson and Indian Academy of Pediatrics representative to

the NTAGI Hib sub-committee. Data from an ICMR study in Anaicut block of

Vellore, obtained under the Right to Information Act were presented. The study

showed that the incidence of all-cause pneumonia was 30 per 1000 children

under-five, and mortality was 0.3 per 1000 children under-five. Thus mortality

is 50 times lower than 14 per 1000 projected by the UNICEF for India4. It was

additionally pointed out that even if mortality was assumed to be as high as 10

per cent (instead of 0.7% observed in the study),

there would be 3 deaths per 1000 children under-five. This study data undercut

one of the main points in the sales pitch for introducing 2 vaccines - the

pneumococal conjugate vaccine and the Hib vaccine in India. Members of the NTAGI

were asked why the data on pneumonia were not included in the NATGI report when

it had selectively quoted nasopharyngeal-carrier data from the same study. The

Chairperson of NTAGI admitted that the results from Anaicut and also that from

Kolkata and Chandigarh in this multi-center study were reviewed by the

sub-committee, but it was left out from the report.

WHO directive on Hib

The latest WHO position paper on Hib says & #65533;Hib vaccine should be included

in all routine immunization programmes " . This suggests that Hib vaccine should

be included in the immunization programme universally, irrespective of an

individual country's disease burden, not withstanding of natural immunity

attained within the country against the disease, and not taking into account the

rights of sovereign States to decide how they use their limited resources. The

mandate and wisdom of issuing such a directive, for a disease that has little

potential of becoming a pandemic, needs to be questioned.

The directive has come after a number of failed attempts to convince the

scientific community of the need for this vaccine in Asia6,7. We present this as

a case study on the visible and invisible pressures brought to bear on

governments to deploy expensive new vaccines.

Invasive Hib in pre-vaccination era

There is a clear distinction between invasive Hib disease (resulting in

pneumonia and meningitis) on the one hand and harmless nasopharyngeal

colonization on the other. The incidence of invasive disease was 500-1000 per

100,000 children under-2 in the Apache reservation and this came down to 22 per

100,000 after immunization8. In Dallas county, Texas, it was 109 per 100,000

children under-59. In Gambia, incidence of Hib meningitis was 200 per 100,000

infants and it fell to 21 with immunization8. On the other hand, the incidence

of invasive disease in Asia, even without immunization was reported as 3 to 9

per 100,000 children-under-510,11.

IBIS (Invasive Bacterial Infections Surveillance) study (India)

It has been suggested that the low incidence of invasive disease in Asia may be

due to early exposure to other bacteria with cross reactive antigens12,13.

Others deny the incidence of Hib in Asia is low and suggest that this is a wrong

impression resulting from the use of inappropriate culture plates14. However,

the IBIS Group using appropriate culture techniques, working in 6 large referral

hospitals over 4 yr (1993-1997), came up with only 125 positive cultures15. To

explain this low culture yield the IBIS group speculated that all cases of

meningitis may not had access to the hospitals. They recommended that community

based studies must be done15.

Community study of Hib meningitis (India)

A community based study looking for Hib meningitis followed (1997-1999). It

showed the Hib meningitis incidence of 0.007 per cent12. In 2002, Dr

Cherian, who is now the WHO Co-ordinator of EPI, wrote that based on the

available data, Hib vaccine could not be recommended for routine use in India16.

Prior antibiotic use and problems with transport of CSF specimens were then

blamed for the poor yield in cultures12. This led investigators to undertake

" probe studies " to identify reduction in disease burden after immunization17.

Asian probe studies

The probe trial in Indonesia from December 1998 to December 2002 found more

cases of pneumonia admitted to hospital among those vaccinated and meningitis

admissions were not reduced significantly either18.

A case-control study on the effectiveness of Hib vaccine in Bangladesh (June

2000 to September 2003) found no significant vaccine effectiveness after 3 doses

of vaccine when either radiologically confirmed pneumonia or meningitis were

compared with matched community controls19. Data dredging and post-hoc analysis

found statistical significance in vaccine effectiveness against pneumonia after

two doses of vaccine. It is recommended that the results of post-hoc analysis

should be explicitly labelled to avoid misleading readers and unadjusted P

values must be interpreted in light of the fact that these are a small and

selected subset of a potentially large group ofP values20. This was not done in

the original report nor has this been explained in the various discourses on

this paper.

Strain replacement with invasive nonserotypable H. influenzae disease

The wisdom of having introduced Hib in the West is now being questioned. The

vaccine has effectively reduced the incidence of Hib disease. However, there has

been a proportionate increase in non-Hib strains, of H. influenzae, including

non-serotypeable strains, causing invasive disease in the post-Hib vaccine

era21,22.

Vaccine efficacy of pentavalent formulation

The NTAGI has recommended that Hib vaccine be introduced in India as pentavalent

vaccine combined with DPT and hepatitis B. A Cochrane meta-analysis has however,

shown that the combination is less effective than the vaccines given

separately23. It is not used for primary immunization in many countries and the

experience with this is therefore limited24.

Coincidental side-effects: cause and effect relation not proven yet

Deaths as side effect: Pentavalent vaccine was introduced in the national

immunization programme in Sri Lanka in January 2008 but after several thousand

doses were administered, it was withdrawn in April 2008 because of 25 serious

adverse reactions that included 5 deaths. A WHO expert panel investigated the

adverse effects and deaths and in its report said that the vaccine was

`unlikely' to have caused the adverse events. It states that although it was not

certain if the vaccine was responsible; the committee could not declare

categorically that the pattern of adverse events was unrelated to the vaccine

and conclusive evidence regarding an alternate cause of the events and outcome

was lacking25. This nuanced WHO report was misleadingly summarized to suggest

that `investigations conducted by WHO did not reveal any causal association

between the events and the Hib containing vaccine'26. Pentavalent vaccine was

then introduced in national

immunization programme of Bhutan in July 2009. Within 2 months, after 8 deaths,

the vaccine was withdrawn in that country27. The NTAGI has not yet withdrawn its

recommendation, nor has the Drug Controller of India sent out advisory asking

doctors to look out for these rare adverse events. The jury is still out on the

evidence about side effects but parents may like to know the odds of benefits

and harms.

Justification for introducing Hib in the National Immunization Programme

The equity argument is often brought up. It is said the vaccine is given by

private practitioners to their well-to-do clientele and it is the responsibility

of government to make it available to the poor. Introduction of this vaccine in

the national programme in the face of proven low incidence of invasive disease,

absence of benefit from Hib vaccination demonstrated in the probe studies from

Asia and the evidence of strain replacement in the West, appears to be a

profligate exercise in futility.

Zubair Lone & M. Puliyel*

Department of Paediatrics

St s Hospital

Delhi 110 054, India

*For correspondence:

puliyel@...

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Lone & Puliyel: IntroducingpentavalentvaccineintheEPI inIndia3

& #65533;

2 INDIAN J MED RES, JULY 2010

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