The potential indirect effect of conjugate pneumococcal vaccines

Abstract

Pneumococcal conjugate vaccines are highly effective in preventing invasive disease in infants and young children, with favorable safety and immunogenicity profiles. These pediatric vaccines have also shown efficacy in reducing cases of non-invasive disease (i.e. otitis media, pneumonia). Recently, pneumococcal conjugate vaccines have demonstrated additional protective qualities that may enhance their use worldwide. For example, they can reduce nasopharyngeal acquisition of vaccine-specific serotypes of Streptococcus pneumoniae, which may in turn reduce the incidence of pneumococcal disease among non-vaccinated individuals; this is termed indirect or herd immunity. Although the emergence of antibiotic-resistant strains has complicated disease management, pneumococcal conjugate vaccines have been shown to protect against pneumococcal disease caused by such strains because most antibiotic-resistant strains are of the serotypes included in these vaccines. Thus, widespread use of these conjugate vaccines may prevent disease by providing both direct and indirect immunity, and may reduce the use of antibiotics and the development of antibiotic resistance worldwide.

Introduction

Streptococcus pneumoniae is among the major bacterial pathogens causing both invasive and non-invasive disease in infants and young children. In North America, the rates of invasive pneumococcal disease are highest in infants, young children, and the elderly [1], [2]. Recent US data from the Active Bacterial Core Surveillance/Emerging Infections Program Network (ABCs) of the Centers for Disease Control and Prevention (CDC) revealed that S. pneumoniae continues to cause approximately 17,000 cases of invasive disease in children younger than 5 years of age every year, including 700 cases of meningitis and 200 deaths [1]. In the United States, the pre-conjugate pneumococcal vaccine rate of invasive pneumococcal disease for this age group of children was comparable to that of invasive Haemophilus influenzae type b (Hib) disease before the introduction of Hib conjugate vaccines. It is also 100-fold greater than the current rates of invasive Hib disease and meningococcal disease (Table 1) [3]. S. pneumoniae is also a major cause of non-invasive disease. It is the leading bacterial cause of acute otitis media in young children in the United States [4], and is responsible for a high proportion of the 4 million deaths per year from pneumonia, nearly all of which occur in developing countries [5].

Asymptomatic nasopharyngeal carriage of pneumococci is highly prevalent among young children and is often the first in a sequence of events that leads to disease in that child or the child’s contacts [6], [7]. As a result, young children play an important role in the transmission of pneumococcal infections within the community because of these high carriage rates and because the disease is easily transmitted through expulsion of respiratory droplets [8]. For example, the presence of children in the household greatly influences pneumococcal carriage rates in adults, with an adult carriage rate of 18–29% in households with children less than 6 years of age compared with a carriage rate of only 6% in households without children [9].

Compounding the issue is the increased global prevalence of antibiotic-resistant strains of S. pneumoniae, which is due in large part to the widespread use of antibiotics in children [10], [11], [12], [13], [14]. Some disease syndromes caused by antibiotic-resistant pneumococci are more difficult to treat with conventional antibiotic therapy. Specifically, otitis media caused by antibiotic-resistant pneumococci can be unresponsive to many conventional drugs [4]. Difficult-to-treat otitis media episodes usually require the use of multiple courses of antibiotics of the same or different classes [15]. The consequence is a vicious cycle of the development of resistant pneumococcal strains [16]. This cycle is one in which the treatment of pneumococcal infections with antibiotics promotes the development and spread of resistant S. pneumoniae, which leads to an increased number of infections with a decreased response to commonly used antibiotics, and sometimes leads to treatment failures. These treatment failures in turn usually result in increased antibiotic use. New antibiotics, against which there is little resistance, may temporarily solve the problem; however, the pathogen ultimately develops resistance to these agents. The only long-term strategies for effective management of pneumococcal disease include prevention through vaccination against pneumococcus, judicious use of antibiotics in the treatment of infections, and reduction of other modifiable risk factors.

Previous experience with the Hib conjugate vaccine has shown that immunization programs not only reduce the incidence of infection among vaccinees, but also reduce the incidence of infections in the non-immunized population (indirect or herd effects). Furthermore, immunization against a bacterial pathogen is likely to decrease the need for antibiotics to treat disease and, in time, should foster more prudent use of antibiotics in the population.

Currently, there are several conjugate vaccines against S. pneumoniae in various stages of laboratory development, clinical evaluation, or currently licensed. This new generation of vaccines comprises 7 serotypes (i.e. 4, 6B, 9V, 14, 18C, 19F, and 23F), 9 serotypes (inclusive of the 7-valent vaccine plus serotypes 1 and 5), or 11 serotypes (inclusive of the 9-valent vaccine plus serotypes 3 and 7F), which are conjugated to a variety of carriers (e.g. a nontoxic diphtheria variant [CRM₁₉₇], tetanus protein, diphtheria toxoid, the outer membrane of Neisseria meningitidis group B (OMP), or an outer membrane protein nontypeable H. influenzae). Unlike pneumococcal polysaccharide vaccines, the conjugated vaccines induce a primary immune response in young children after one or more doses (depending on the serotype evaluated) and an anamnestic (i.e. booster) response after subsequent doses because of the T-cell-dependent nature of the immune response [17], [18], [19], [20], [21], [22], [23], [24].

The focus of this article is to: (1) review briefly the efficacy and safety data of various conjugate pneumococcal vaccines; (2) discuss their potential role as vectors for indirect immunity in pneumococcal disease; and (3) discuss their possible impact on the use of and need for antibiotic therapy.