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Response to a comment by Vashisht and Jain by the Study Investigators

Posted by aroca on 08 Nov 2011 at 22:13 GMT

Vashisht and Jain question the ethics of the trial on PCV-7 we carried out in The Gambia and whose results have been reported recently in PLoS Med [1]. They have four areas of concern which we will address in turn.
1. Pneumococcal conjugate vaccines are not intended for adults and adults will not benefit from vaccination with these vaccines. A single dose of pneumococcal polysaccharide vaccine is recommended for the elderly and other high risk groups in Western countries and one dose provides substantial protection against invasive pneumococcal disease. In the elderly, the 23-valent polysaccharide vaccine is generally preferred to a conjugate vaccine because of its larger number of components. Nevertheless, conjugate vaccines are at least as immunogenic as polysaccharide vaccine in adults [2] and they will almost certainly provide as much protection against serotypes in the vaccine as seen with polysaccharide vaccines. For example, a recent study undertaken in Malawi by French et al [3] showed that two doses of PCV-7 in HIV infected adults gave 74% protection against invasive pneumococcal disease. On these grounds the European Medicines Agency (EMEA) – a European regulatory agency for evaluation of medical products - recently approved the use of a 13-valent pneumococcal conjugate vaccine (PCV-13) for adults. Therefore, all the adults who participated in our trial will have obtained some protection against either pneumococcal or meningococcal disease. The fact that adults who received the pneumococcal conjugate vaccine did obtain some benefit is strongly suggested by our detection of a lower prevalence of carriage of pneumococci of vaccine-type in adults in pneumococcal vaccinated communities [1].
2. Pneumococcal vaccination will have selected for penicillin resistance. Vashisht and Jain suggest that pneumococcal vaccination will have selected for penicillin resistance. It is very unlikely that this has been the case and all the evidence suggests the opposite [4]. The strains most resistant to penicillin occur among serotypes included in PCV-7 as these are those commonly found in the nasopharynx and thus under the highest antibiotic pressure. Therefore, vaccination against these strains reduces the overall number of penicillin resistant strains in the community, at least in the short- to medium term [4,5]. There have been some reports of an increase in antibiotic resistance in some non-PCV-7 serotypes, such as 19A, but this has been observed in both vaccinated and not-vaccinated communities [5–7].
3. The nature of the consent process. Vashisht and Jain have concerns over the consent process employed in this study. We can reassure them that every effort was made to obtain fully informed consent from both the study communities and from individual participants in the trial utilizing community meetings, discussions with community leaders and collection of written, witnessed consent forms from every individual or parent or guardian of a participating child. Both community and individual consent forms specifically mentioned the potential for serotype replacement. The individual consent form stated “MRC would want to know whether or not there would be changes in the types of this germ in the throat when the vaccine is used in a large scale in the future” and the community consent form stated “Therefore it is important to find out whether or not these other similar germs that are capable of causing pneumonia can replace the germs, which have been eliminated”. There were no refusals among the communities invited to join the study. Although PCV-7 was a licensed product we had some individual refusals and vaccine coverage in the vaccinated arm oscillated between 85% and 92% depending on the survey as stated in the first paragraph of the results in the paper. More information is shown in Supplementary table 2.
4. The duration of follow-up. Vashisht and Jain are concerned that the duration of follow-up described in our paper (two years) was too short to detect serotype replacement and we agree that this may be the case. However, we have recently conducted a four year follow-up, whose results will be presented shortly. This showed a persistent reduction in carriage of pneumococci of vaccine serotype in both groups of villages and no increase in carriage with pneumococci of non-vaccine serotype. Prevalence of carriage of non-vaccine serotypes did not differ between vaccinated and control communities. The effect of whole community vaccination on newborns too young to be vaccinated has also been studied and these results will be available shortly.
We hope that we have been able to allay the concerns of Vashisht and Jain about this trial, satisfy them that this study was conducted to high ethical standards and that it provided all participants with some benefit at minimal risk. The trial has helped us to understand better how pneumococcal conjugate vaccines can be used to prevent mortality and morbidity from pneumococcal disease in the developing world.

Reference List
1. Roca A, Hill PC, Townend J, Egere U, Antonio M, Bojang A, Akisanya A, Litchfield T, Nsekpong DE, Oluwalana C, Howie SR, Greenwood B, Adegbola RA (2011) Effects of Community-Wide Vaccination with PCV-7 on Pneumococcal Nasopharyngeal Carriage in The Gambia: A Cluster-Randomized Trial. PLoS Med 8: e1001107. 10.1371/journal.pmed.1001107 [doi];PMEDICINE-D-11-00302 [pii].
2. Jackson LA, Janoff EN (2008) Pneumococcal vaccination of elderly adults: new paradigms for protection. Clin Infect Dis 47: 1328-1338. 10.1086/592691 [doi].
3. French N, Gordon SB, Mwalukomo T, White SA, Mwafulirwa G, Longwe H, Mwaiponya M, Zijlstra EE, Molyneux ME, Gilks CF (2010) A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults. N Engl J Med 362: 812-822. 362/9/812 [pii];10.1056/NEJMoa0903029 [doi].
4. Dagan R, Klugman KP (2008) Impact of conjugate pneumococcal vaccines on antibiotic resistance. Lancet Infect Dis 8: 785-795. S1473-3099(08)70281-0 [pii];10.1016/S1473-3099(08)70281-0 [doi].
5. Dagan R (2009) Impact of pneumococcal conjugate vaccine on infections caused by antibiotic-resistant Streptococcus pneumoniae. Clin Microbiol Infect 15 Suppl 3: 16-20. CLM2726 [pii];10.1111/j.1469-0691.2009.02726.x [doi].
6. Pelton SI, Loughlin AM, Marchant CD (2004) Seven valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates. Pediatr Infect Dis J 23: 1015-1022. 00006454-200411000-00009 [pii].
7. van Gils EJ, Veenhoven RH, Hak E, Rodenburg GD, Keijzers WC, Bogaert D, Trzcinski K, Bruin JP, van AL, van der Ende A, Sanders EA (2010) Pneumococcal conjugate vaccination and nasopharyngeal acquisition of pneumococcal serotype 19A strains. JAMA 304: 1099-1106. 304/10/1099 [pii];10.1001/jama.2010.1290 [doi].

No competing interests declared.