Abstract
Background: The effect of 7-valent pneumococcal conjugate vaccine (PCV) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci. The potential indirect protection of 10-valent PCV (PCV10) in a developing country setting is unknown. We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria. Methods: PCV10 was introduced into the infant vaccination programme in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. We did annual cross-sectional carriage studies among an age-stratified, random population sample in the 2 years before and 2 years after PCV10 introduction. A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations. Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression. Findings: About 500 individuals were enrolled each year (total n=2031). Among children younger than 5 years, the baseline (2009-10) carriage prevalence was 34% for vaccine-serotype Streptococcus pneumoniae, 41% for non-vaccine-serotype Streptococcus pneumoniae, and 54% for non-typeable Haemophilus influenzae. After PCV10 introduction (2011-12), these percentages were 13%, 57%, and 40%, respectively. Adjusted prevalence ratios were 0·36 (95% CI 0·26-0·51), 1·37 (1·13-1·65), and 0·62 (0·52-0·75), respectively. Among individuals aged 5 years or older, the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 (95% CI 0·18-0·62) and 1·13 (0·92-1·38), respectively. There was no change in prevalence ratio for Staphylococcus aureus (adjusted prevalence ratio for those <5 years old 1·02, 95% CI 0·52-1·99, and for those ≥5 years old 0·90, 0·60-1·35). Interpretation: After programmatic use of PCV10 in Kilifi, carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals. These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease. Funding: GAVI Alliance and Wellcome Trust.
| Original language | English (US) |
|---|---|
| Pages (from-to) | e397-e405 |
| Journal | The Lancet Global Health |
| Volume | 2 |
| Issue number | 7 |
| DOIs | |
| State | Published - 2014 |
ASJC Scopus subject areas
- Medicine(all)
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In: The Lancet Global Health, Vol. 2, No. 7, 2014, p. e397-e405.
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TY - JOUR
T1 - Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya
T2 - Findings from cross-sectional carriage studies
AU - Hammitt, Laura L.
AU - Akech, Donald O.
AU - Morpeth, Susan C.
AU - Karani, Angela
AU - Kihuha, Norbert
AU - Nyongesa, Sammy
AU - Bwanaali, Tahreni
AU - Mumbo, Edward
AU - Kamau, Tatu
AU - Sharif, Shahnaaz K.
AU - Scott, J. Anthony G.
N1 - Funding Information: We report rapid, significant reductions in vaccine serotype nasopharyngeal carriage at a population level in Kilifi, Kenya, after introduction of PCV10 into the routine infant vaccination schedule accompanied by a catch-up campaign for children younger than 5 years. To our knowledge, this is the first study to report the effects on carriage of a national PCV vaccination programme in a GAVI Alliance-eligible developing country ( ). Although pneumococcal carriage is often asymptomatic and benign, it is a necessary precursor in the development of invasive disease. Because of this causal link, vaccine effect on carriage is an important marker of vaccine-induced protection against disease in children and adults. panel 13 About 18 months after the introduction of PCV10, we noted a 64% reduction in vaccine-serotype S pneumoniae carriage among children younger than 5 years, 79% of whom had received at least one dose of PCV10. In comparison, in Alaska, USA, 3 years after introduction of 7-valent PCV (PCV7), a 91% reduction in vaccine serotype carriage was noted among Alaska Native children aged 5 years or younger, more than 99% of whom had received at least one dose of PCV7. 33 In both settings, PCV was introduced with a catch-up campaign. In a large cluster-randomised study in The Gambia, 39 in which widespread PCV7 vaccination was undertaken, there was a 56% reduction in vaccine serotype carriage in children aged 2–5 years living in villages where children younger than 30 months were vaccinated and a 74% reduction in villages where all residents receive at least one dose of PCV7. Within 2 years after PCV7 was introduced into the public immunisation programme for infants without a catch-up campaign in a South African community with high HIV prevalence, vaccine serotype carriage was reduced by 50% among children younger than 2 years, 51% of whom had received three doses of PCV7. 40 In the Netherlands, 3 years after introduction of PCV7, without a catch-up campaign, vaccine serotype carriage was reduced by 80–90% among vaccinated children aged between 11 months and 24 months. 34 In Portugal, 4 years after PCV7 became available, in children aged 4 months to 6 years, 57% of whom had received PCV7, vaccine serotype carriage was reduced by 78%. 35 The above-mentioned studies show a substantial effect on vaccine serotype carriage 1·5–4 years after introduction of PCV with and without a catch-up campaign, with vaccine coverage in the target age group ranging between 50% and 100%. Reductions in carriage have been matched by reductions in invasive pneumococcal disease in settings where such data are available, including the KHDSS, where 1 year after PCV10 introduction, the vaccine effectiveness was estimated to be 72% (95% CI 34–88) against vaccine-serotype invasive pneumococcal disease in children aged younger than 5 years. 36–38,41 In addition to the effect in the vaccine target age group, we noted a 66% reduction in vaccine serotype carriage adjusted prevalence in individuals aged 5 years or older. This finding is consistent with findings among Alaska Native people, in whom a 68% reduction in vaccine serotype carriage was reported among people aged at least 18 years about 3 years after introduction of PCV7. 33 The reductions in vaccine serotype carriage in the non-target age group in Kilifi were apparent in the first post-PCV10 survey (2011), when coverage with at least one dose of PCV10 among children younger than 5 years was 63% in the KHDSS and 69% among study participants. Reasons for the difference in the vaccine coverage estimates for study participants compared with all KHDSS children are as follows: (1) the time lag between the random selection of potential participants and their enrolment in the study caused our sample of the very youngest age group (0–12 months) to be skewed towards the upper end of this bracket when children were more likely to have been vaccinated; (2) our study captured vaccinations given outside the area covered by the vaccine registry; and (3) some of the migrant population—who generally have lower levels of vaccine coverage—would have been lost after random selection in our study. Nonetheless, our findings suggest that substantial indirect effects occur when two-thirds of children younger than 5 years are vaccinated and imply that the indirect protection against invasive pneumococcal disease noted in the USA and UK can probably be replicated in developing countries. In other settings, the reduction in vaccine serotype carriage prevalence after programmatic introduction of PCVs has been matched by a reciprocal increase in carriage prevalence of non-vaccine serotypes (ie, serotype replacement carriage) such that the overall pneumococcal carriage prevalence, typically, is unchanged from baseline. However, serotype replacement in the nasopharynx has had a variable effect on invasive pneumococcal disease. 5,10 In most settings, serotype replacement invasive pneumococcal disease has been minimal, whereas in some settings it has almost negated the beneficial effect of PCVs in some subgroups of the population. We noted a significant increase in carriage of non-vaccine-serotype pneumococci among children younger than 5 years; however, because the magnitude of the decline in vaccine serotype carriage was greater, there was a slight decline in overall S pneumoniae carriage prevalence in the PCV10 period. The reduction in overall pneumococcal carriage in children is likely to be attributable to the vaccine itself, rather than to underlying variations in carriage, because analyses of the change in carriage prevalence for all pneumococci over the 4 years did not identify a significant decline in prevalence after adjusting for vaccine effect. Although non-vaccine serotype carriage increased significantly in children younger than 5 years, the increase was not statistically significant in people aged 5 years or older. Children are likely to experience more rapid, direct clearance of vaccine serotype carriage and subsequent replacement carriage, whereas adults experience delayed, indirect clearance. Thus, replacement carriage in adults is probably delayed. Two other studies in Africa—a cluster-randomised trial of PCV in The Gambia 39 and an observational ecological study after programmatic introduction of PCV7 in South Africa 40 —found that non-vaccine serotype carriage declined in adolescents and adults after PCV use in children. However, these findings are subject to several limitations including the short period of follow-up and changes in HIV treatment regimens in South Africa, and an intercurrent community-wide azithromycin campaign in The Gambia. Long-term surveillance is essential to understand PCV-induced changes in non-vaccine serotype carriage and disease. In serotype-specific analyses, we noted no effect on carriage of the serotypes 6A or 19A in the target age group. This finding is consistent with data from clinical trials that show that PCV10 does not induce a robust antibody response against these strains. 42 Only the predominant colony appearance of pneumococcus was serotyped from each nasopharyngeal swab, so serotype-specific variations do not account for changes that might have occurred among the non-dominant strains carried by an individual. However, assuming that the probability of sampling a strain is proportional to the frequency of that serotype in the nasopharynx then the present study is of a random sample of strains in a random sample of individuals and this limitation should not affect our conclusions about vaccine effectiveness. Carriage is expected to be in flux in the first few years of vaccine use and carriage prevalence will probably continue to change before reaching equilibrium. 43,44 We noted a significant reduction in nasopharyngeal carriage of non-typeable H influenzae among participants younger 5 years and at least 5 years old in the vaccine period compared with baseline. However, the role of PCV10 as the causative agent of this change is questionable since non-typeable H influenzae carriage prevalence seemed to rebound in year 2 of the vaccine period and we did not find an association between an individual's vaccination status and carriage of non-typeable H influenzae (by comparing individuals with at least two doses to those with zero or one dose). Findings from early clinical trials suggested that use of an 11-valent protein-D conjugate vaccine reduced the carriage prevalence of vaccine-serotype and non-typeable H influenzae , although the decline in non-typeable H influenzae carriage was not significant when molecular methods were used to differentiate non-typeable H influenzae from the closely-related H haemolyticus . 16,45 In long-term follow-up, lower non-typeable H influenzae carriage prevalence in vaccine recipients compared with controls was documented at about 2 years of age but at no other timepoint. 46 Other clinical trials of PCV10 have not documented a significant, consistent effect of vaccination on carriage of non-typeable H influenzae . 47–49 Although the prevalence of non-typeable H influenzae might have been higher had we collected an oropharyngeal swab in addition to a nasopharyngeal swab, our methods were similar across years of the study, thus allowing comparison between periods before and after vaccination. 50 We reported no change in the carriage prevalence of S aureus after introduction of PCV10. By contrast, findings from several studies have suggested an inverse relation between carriage of S pneumoniae and S aureus, 17–20 and one population-level assessment in the Netherlands reported an increase in S aureus carriage after introduction of PCV7. 51 Potential explanations for this difference include variations in the nasopharyngeal microbiome across populations and the competition dynamics that ensue after reductions in pneumococcal carriage in a rural developing country setting. S aureus was cultured in our study, and in most of the comparator studies cited earlier, from the posterior nasopharynx. Cultures of the anterior nares might be more appropriate to fully characterise the effect of the vaccine on S aureus. The period after vaccine surveillance in the present study is brief and the sustainability of effects (or absence of effects) on carriage of various different bacteria can only be identified after a longer period of surveillance. We intend to extend surveillance for at least 3 more years, but have reported early results because the catch-up campaign provided additional maturity to the programme and the vaccine effects are large. In presenting measures of VE carr , we used the term effectiveness to describe the magnitude of the effect of the vaccine in the total population (that we sampled randomly) under the short-term conditions of rapid introduction with high coverage. The effect of the programme will evolve over time and will be determined by both the coverage in infants and the age structure of coverage among the total carrier population. In presenting the prevalence ratio, we have assumed that the key risk for disease is total carriage prevalence. If the key risk is acquisition of carriage, then the odds ratio might provide a more accurate estimate. However, the two methods (prevalence ratio and odds ratio) yielded similar results in this analysis. PCVs are being introduced rapidly across developing countries, although there is, as yet, limited evidence of their operational effect. PCV10, in particular, has not been studied in any national vaccination programme. This study has shown that introduction of PCV10 in a developing country setting, with a catch-up campaign, has led to a two-thirds reduction in carriage prevalence of vaccine-serotype pneumococci both in children targeted for vaccination and in older people who were not vaccinated. The effect reported in children provides convincing functional evidence that the vaccine is inducing immunological protection at a level sufficient to prevent invasive disease. The effect in older children and adults suggests that the childhood PCV10 programme is reducing transmission of vaccine-serotype pneumococci within the population and this is likely to lead to a reduction in vaccine-serotype invasive pneumococcal disease across all age groups (ie, herd protection). Contributors LLH and JAGS were involved in the design and conduct of the study, data analysis, data interpretation, and writing of the manuscript. DOA was involved in data collection, data analysis, and laboratory analysis. SCM was involved in laboratory analysis, data interpretation, and writing of the manuscript. AK and SN were involved in laboratory analysis and data analysis. NK was involved in data collection and data analysis. TB, EM, TK, and SKS were involved in design and conduct of the study. Declaration of interests LLH has received research funding from GlaxoSmithKline Biologicals and Pfizer. JAGS has received research funding form GlaxoSmithKline Biologicals and support for travel or accommodation at a scientific meeting sponsored by Merck. All other authors declare no competing interests. Acknowledgments We thank the study participants, the Ministry of Health District Health Management Team in Kilifi County, and the dedicated team of fieldworkers, data managers, and laboratory scientists who worked on this study. JAGS is funded by a fellowship from the Wellcome Trust of Great Britain ( number 098532 ). This paper is published with the permission of the Director of the Kenya Medical Research Institute. Funding Information: This work was done under a collaborative arrangement with the PenumoADIP at Johns Hopkins Bloomberg School of Public Health and funded by the GAVI Alliance. This study was done at a research unit funded by the Wellcome Trust of Great Britain. The funders of the study had no role in study design, data collection, data analysis, writing of the report, or the decision to submit manuscript for publication. LLH had full access to all the data in the study, takes responsibility for the integrity of the data and the accuracy of the data analysis, and had final responsibility for the decision to submit for publication. Publisher Copyright: © 2014 Hammitt et al. Open Access article distributed under the terms of CC BY.
PY - 2014
Y1 - 2014
N2 - Background: The effect of 7-valent pneumococcal conjugate vaccine (PCV) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci. The potential indirect protection of 10-valent PCV (PCV10) in a developing country setting is unknown. We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria. Methods: PCV10 was introduced into the infant vaccination programme in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. We did annual cross-sectional carriage studies among an age-stratified, random population sample in the 2 years before and 2 years after PCV10 introduction. A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations. Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression. Findings: About 500 individuals were enrolled each year (total n=2031). Among children younger than 5 years, the baseline (2009-10) carriage prevalence was 34% for vaccine-serotype Streptococcus pneumoniae, 41% for non-vaccine-serotype Streptococcus pneumoniae, and 54% for non-typeable Haemophilus influenzae. After PCV10 introduction (2011-12), these percentages were 13%, 57%, and 40%, respectively. Adjusted prevalence ratios were 0·36 (95% CI 0·26-0·51), 1·37 (1·13-1·65), and 0·62 (0·52-0·75), respectively. Among individuals aged 5 years or older, the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 (95% CI 0·18-0·62) and 1·13 (0·92-1·38), respectively. There was no change in prevalence ratio for Staphylococcus aureus (adjusted prevalence ratio for those <5 years old 1·02, 95% CI 0·52-1·99, and for those ≥5 years old 0·90, 0·60-1·35). Interpretation: After programmatic use of PCV10 in Kilifi, carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals. These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease. Funding: GAVI Alliance and Wellcome Trust.
AB - Background: The effect of 7-valent pneumococcal conjugate vaccine (PCV) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci. The potential indirect protection of 10-valent PCV (PCV10) in a developing country setting is unknown. We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria. Methods: PCV10 was introduced into the infant vaccination programme in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. We did annual cross-sectional carriage studies among an age-stratified, random population sample in the 2 years before and 2 years after PCV10 introduction. A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations. Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression. Findings: About 500 individuals were enrolled each year (total n=2031). Among children younger than 5 years, the baseline (2009-10) carriage prevalence was 34% for vaccine-serotype Streptococcus pneumoniae, 41% for non-vaccine-serotype Streptococcus pneumoniae, and 54% for non-typeable Haemophilus influenzae. After PCV10 introduction (2011-12), these percentages were 13%, 57%, and 40%, respectively. Adjusted prevalence ratios were 0·36 (95% CI 0·26-0·51), 1·37 (1·13-1·65), and 0·62 (0·52-0·75), respectively. Among individuals aged 5 years or older, the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 (95% CI 0·18-0·62) and 1·13 (0·92-1·38), respectively. There was no change in prevalence ratio for Staphylococcus aureus (adjusted prevalence ratio for those <5 years old 1·02, 95% CI 0·52-1·99, and for those ≥5 years old 0·90, 0·60-1·35). Interpretation: After programmatic use of PCV10 in Kilifi, carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals. These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease. Funding: GAVI Alliance and Wellcome Trust.
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U2 - 10.1016/S2214-109X(14)70224-4
DO - 10.1016/S2214-109X(14)70224-4
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C2 - 25103393
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SN - 2214-109X
VL - 2
SP - e397-e405
JO - The Lancet Global Health
JF - The Lancet Global Health
IS - 7
ER -