Pneumococcal conjugate vaccine is efficacious and effective in reducing the burden of pneumonia
Shabir A Madhi a, Orin S Levine b, Thomas Cherian c
While Chowdhary & Puliyel1 are correct that there has been a non-significant reduction in clinically diagnosed pneumonia in the vaccine-efficacy trials conducted to date, their assertion that pneumococcal conjugate vaccine (PCV) does not reduce severe pneumonia or reduce mortality in the Gambia is fundamentally flawed. Updated estimates indicate that there are 155.8 million clinical episodes of pneumonia globally, which contribute to approximately 1.9 million deaths, 70% of which occur in Africa and south-east Asia.2 The major drawback in evaluating the efficacy of PCV against “clinical pneumonia” is the lack of specificity of this clinical outcome measure that was designed for case management of pneumonia. The choice of clinical pneumonia as an endpoint is therefore biased in favour of high sensitivity, at the expense of specificity, in contrast to the more specific endpoints usually used in vaccines efficacy trials. Indeed, a large proportion of the cases that meet the case definitions for clinical pneumonia have a low positive predictive value and are, therefore, not pneumonia.3 In the case management strategy, one accepts a level of over-treatment because of the important mortality reduction benefits. Nevertheless, that pneumococci contribute to significant pneumonia-related mortality is evident in the success of the WHO case-management strategy of pneumonia, which is premised upon early antibiotic therapy especially targeting S. pneumoniae and is associated with a 36% reduction in pneumonia-mortality.4
On the other hand, radiologically-confirmed pneumonia is a relatively more specific measure of bacterial pneumonia and so efficacy of vaccine on this outcome measure is a better indicator of effect on pneumonia mortality. This outcome was indeed the primary outcome measure for determining efficacy of the vaccine against pneumonia, rather than the less specific measure of clinical pneumonia. The vaccine trials were thus not powered to measure efficacy against clinical pneumonia and it is not surprising that the efficacy estimate did not reach statistical significance. Furthermore, low specificity of the outcome measure leads to misclassification and a substantial underestimation of vaccine efficacy.5
The case fatality ratio in the Gambia trial was significantly greater in children with radiologically-confirmed pneumonia (3%) compared with clinical pneumonia cases that do not fulfil the criteria of radiologically-confirmed pneumonia (0.8–1.2%) even with access to antibiotic therapy.6 In the absence of antibiotics, this difference may have been even greater. Radiologically-confirmed pneumonia accounts for as much as 16.7–34% of cases of clinical pneumonia,6–8 The higher case fatality rate of radiologically-confirmed pneumonia and the higher impact of vaccine on this clinical outcome suggests that the impact of vaccine is more than a “minimal” contribution. Additionally, PCV is able to reduce pneumonia with an abnormal chest X-ray, but not defined as “radiologically-confirmed”, by 1.2–7% to 30–32% when the specificity of this outcome is improved for bacterial pneumonia by using a C-reactive protein of ≥ 40 mg/l as an adjunctive marker.9,10 Thus, the impact of vaccine on true pneumonia and pneumonia mortality is substantially greater than is indicated by the efficacy against “clinical pneumonia”.
Additionally, vaccine-efficacy trials may underestimate the public health benefit of vaccines, as indicated by the indirect herd-protection observed following introduction of PCV into the United States of America11 and, more recently, the 39% reduction in the burden of clinical pneumonia hospitalization after PCV-introduction,12 compared to a non-significant 7% reduction in northern California during the vaccine-efficacy trial.13 It is only through the phased introduction of PCV, which has been shown to be safe and efficacious in children from diverse settings, that the true public health benefit of PCV would be realized in developing countries. This would however need to be coupled with robust surveillance systems to evaluate changes in the epidemiology of pneumonia before and after its introduction in representative populations of different regions of the world.
The mortality benefit in the Gambian study was not evident only within 1 week of vaccination, but in fact mainly from 12 months onward when 238 (72.1%) of the 330 PCV-recipients’ deaths and 289 (73.5%) of the placebo recipients’ deaths occurred.14 The rate of mortality within 7 days of any dose of study vaccine (n = 12; 0.15%) and placebo (n = 15; 0.18%; P = 0.55) did not differ between the two groups, and their reported incidence calculations are incorrect. The higher rate of reactive airway disease observed in the South African study was not evident upon subsequent analysis following extended follow up of the cohort until an average of 6.3 years of age (S Madhi, personal communication). Additionally, the higher initially reported risk (1.3 per 1000 children) needs to be weighed against the net reduction of disease prevented, which was 3.6 per 1000 child years against radiologically-confirmed pneumonia alone.15
In conclusion, while we agree with the assertion that the use of PCV in developing countries needs to be weighed in relation to its cost and benefit, we believe that the potential benefit of PCV in developing countries is beyond question, as indicated by the WHO recommendation on PCV.16 Nevertheless, it is essential that the introduction of PCV be coupled with adequate surveillance at least in representative communities of regions in which it is introduced to fully establish the potential to public health of the vaccine. ■
- Chowdharya S, Puliyela J. Incidence of pneumonia is not reduced by pneumococcal conjugate vaccine. Bull World Health Organ 2008; 86: 816-.
- Rudan I, Tomaskovic L, Boschi-Pinto C, Campbell H. Global estimate of the incidence of clinical pneumonia among children under five years of age. Bull World Health Organ 2004; 82: 895-903 pmid: 15654403.
- Cherian T, John TJ, Simoes E, Steinhoff MC, John M. Evaluation of simple clinical signs for the diagnosis of acute lower respiratory tract infection. Lancet 1988; 2: 125-8 doi: 10.1016/S0140-6736(88)90683-6 pmid: 2899187.
- Sazawal S, Black RE. Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials. Lancet Infect Dis 2003; 3: 547-56 doi: 10.1016/S1473-3099(03)00737-0 pmid: 12954560.
- Jaffar S, Leach A, Smith PG, Cutts F, Greenwood B. Effects of misclassification of causes of death on the power of a trial to assess the efficacy of a pneumococcal conjugate vaccine in The Gambia. Int J Epidemiol 2003; 32: 430-6 doi: 10.1093/ije/dyg082 pmid: 12777432.
- Enwere G, Cheung YB, Zaman SM, Akano A, Oluwalana C, Brown O, et al., et al. Epidemiology and clinical features of pneumonia according to radiographic findings in Gambian children. Trop Med Int Health 2007; 12: 1377-85 pmid: 18045264.
- Madhi SA, Kuwanda L, Cutland C, Klugman KP. The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children. Clin Infect Dis 2005; 40: 1511-8 doi: 10.1086/429828 pmid: 15844075.
- Magree HC, Russell FM, Sa’aga R, Greenwood P, Tikoduadua L, Pryor J, et al., et al. Chest X-ray-confirmed pneumonia in children in Fiji. Bull World Health Organ 2005; 83: 427-33 pmid: 15976893.
- Madhi SA, Klugman KP. World Health Organisation definition of “radiologically-confirmed pneumonia” may under-estimate the true public health value of conjugate pneumococcal vaccines. Vaccine 2007; 25: 2413-9 doi: 10.1016/j.vaccine.2006.09.010 pmid: 17005301.
- Cheung YB, Zaman SM, Ruopuro ML, Enwere G, Adegbola RA, Greenwood B, et al., et al. C-reactive protein and procalcitonin in the evaluation of the efficacy of a pneumococcal conjugate vaccine in Gambian children. Trop Med Int Health 2008; 13: 603-11 pmid: 18331385.
- Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease — United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005; 54: 893-7 pmid: 16163262.
- Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002; 21: 810-5 doi: 10.1097/00006454-200209000-00005 pmid: 12352800.
- Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al., et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005; 365: 1139-46 doi: 10.1016/S0140-6736(05)71876-6 pmid: 15794968.
- Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341-8 doi: 10.1056/NEJMoa035060 pmid: 14523142.
- Pneumococcal conjugate vaccine for childhood immunization – WHO position paper. Wkly Epidemiol Rec 2007; 82: 93-104 pmid: 17380597.
- Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Chris Hani Baragwanth Hospital, Bertsham 2013, South Africa.
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland.