Elsevier

The Lancet

Volume 378, Issue 9807, 3–9 December 2011, Pages 1962-1973
The Lancet

Review
Serotype replacement in disease after pneumococcal vaccination

https://doi.org/10.1016/S0140-6736(10)62225-8Get rights and content

Summary

Vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) has significantly reduced the burden of pneumococcal disease and has had an important public health benefit. Because this vaccine targets only seven of the more than 92 pneumococcal serotypes, concerns have been raised that non-vaccine serotypes (NVTs) could increase in prevalence and reduce the benefits of vaccination. Indeed, among asymptomatic carriers, the prevalence of NVTs has increased substantially, and consequently, there has been little or no net change in the bacterial carriage prevalence. In many populations, pneumococcal disease caused by NVT has increased, but in most cases this increase has been less than the increase in NVT carriage. We review the evidence for serotype replacement in carriage and disease, and address the surveillance biases that might affect these findings. We then discuss possible reasons for the discrepancy between near-complete replacement in carriage and partial replacement for disease, including differences in invasiveness between vaccine serotypes. We contend that the magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and biases in the disease surveillance systems that could underestimate the true amount of replacement. We conclude by discussing the future potential for serotype replacement in disease and the need for continuing surveillance.

Introduction

Widespread use of heptavalent pneumococcal conjugate vaccine (PCV7; Prevnar, Wyeth, Madison, NJ, USA) has significantly reduced the burden of pneumococcal disease in many populations.1, 2, 3, 4, 5, 6, 7, 8 PCV7 targets seven of the more than 92 serotypes (so-called “vaccine types”) of Streptococcus pneumoniae (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F), whereas the newly available PCV13 covers these seven serotypes as well as serotypes 1, 3, 5, 6A, 7F, and 19A. PCV7 has greatly reduced the incidence of disease caused by these serotypes both in vaccinated young children and among non-vaccinated groups due to herd immunity, and has led to public health benefits throughout the developed world where it has been used. In light of this evidence and of clinical trials done in developing countries that show substantial benefits,9, 10, 11 conjugate vaccines are being introduced more widely throughout the world. However, the epidemiological effect of broad-scale use of conjugate vaccines in new settings can be difficult to predict, so careful monitoring of disease burden will be needed to assess the initial and long-term effects of mass vaccination in each region where the vaccine is introduced.

The pneumococcal population has changed since the widespread introduction of PCV7. Non-vaccine types (NVTs) have increased among asymptomatic carriers in a process dubbed “serotype replacement”,12, 13 and to a lesser extent, NVTs have increased as causes of invasive pneumococcal disease (IPD). In nasopharyngeal carriage, we define serotype replacement as an increase in the proportion of individuals in a population who harbour NVTs in their nasopharynx after vaccine introduction. For IPD, serotype replacement is defined as an increase in the incidence of IPD caused by NVTs after vaccine introduction. Although the reported magnitude of this increase in disease among NVTs has been relatively modest in most countries, such changes have the potential to dampen the overall public-health benefit of the vaccine.

A key question is why does serotype replacement seem to be complete among asymptomatic carriers whereas replacement in disease seems incomplete? In other words, why has the vaccine successfully reduced the burden of pneumococcal disease whereas the prevalence of bacterial carriage has not changed? Understanding this issue will be crucial to enable us to predict the effects of future pneumococcal vaccination programmes, particularly in developing countries where pneumococcal epidemiology differs from that in Europe and the USA. We therefore review the evidence for serotype replacement in carriage and disease, assess potential biases in the data and reasons for heterogeneity between studies, discuss the biological and epidemiological features of the serotypes, and address the relative contributions of vaccination and other factors to the increases in NVTs. We also discuss the potential effects of serotype replacement after the introduction of conjugate vaccines in diverse settings.

Section snippets

Nasopharyngeal carriage: the precursor to IPD

The first reports of serotype replacement came from a double-blind, randomised placebo-controlled trial (RCT) from The Gambia that showed that carriage of vaccine types significantly declined in vaccinated infants, while carriage of NVTs significantly increased.14 As a result of this change, the net effect on carriage prevalence in the trial was small. An Israeli vaccine trial did not show a significant effect of serotype replacement in carriage among vaccinated children,15 but a subsequent

Background

Many studies have assessed serotype-specific IPD incidence before and after the introduction of PCV7 (table), but the measured effect of vaccination on NVT disease has been inconsistent. In classic, individually randomised trials, only a small proportion of the population is typically vaccinated. Therefore, such trials have a small effect on the overall bacterial population by contrast with what will occur with mass vaccination. For this reason, individually randomised trials are not designed

Background

Now that we have reviewed the evidence for serotype replacement in carriage and disease, we return to the questions of why serotype replacement has been complete in carriage but not in disease, how much the incidence of IPD has truly been affected by vaccination and replacement, and what factors are likely to be responsible for the increase in NVTs.

Discrepancy in magnitude of replacement between carriage and disease

The incidence of IPD caused by a particular serotype is the product of the incidence rate of new carriage episodes with that serotype, and the

Vaccination in developing countries

The studies reviewed here show that despite the increased incidence of NVTs that cause IPD in many populations, PCV7 has had a significant positive benefit on paediatric disease, especially in children younger than 2 years, in whom it is in widespread use. The measured benefit clearly varies across populations; some of this variation is real, and indicates host and pathogen population characteristics. The epidemiology of IPD in developing countries differs from that in other parts of the world.

Future prospects for serotype replacement in disease

The evidence presented here strongly support the notion that serotype replacement has occurred in IPD in most populations and is caused by the vaccine. We should assume that the introduction of new conjugate vaccine formulations in the future will again be met with complete serotype replacement among carriers and some amount of replacement in disease that will partly depend on the invasiveness of the colonising serotypes. The recently introduced 13-valent vaccine has the potential to have

Search strategy and selection criteria

We identified relevant studies on serotype replacement in disease with a comprehensive search of PubMed (by use of combinations of the search terms “pneumococ*”, “Streptococcus pneumoniae”, “PCV7”, “conjugate”, and “serotype”) and the reference lists of selected articles. Because we were interested in the question of population-wide serotype dynamics, we included only studies that reported the incidence of vaccine-type and NVT disease in the general population (ie, nationwide or hospital-based

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