Serotype-independent pneumococcal vaccines

Abstract

Streptococcus pneumoniae remains an important cause of disease with high mortality and morbidity, especially in children and in the elderly. The widespread use of the polysaccharide conjugate vaccines in some countries has led to a significant decrease in invasive disease caused by vaccine serotypes, but an increase in disease caused by non-vaccine serotypes has impacted on the overall efficacy of these vaccines on pneumococcal disease. The obvious solution to overcome such shortcomings would be the development of new formulations that provide serotype-independent immunity. This review focuses on the most promising approaches, including protein antigens, whole cell pneumococcal vaccines, and recombinant bacteria expressing pneumococcal antigens. The protective capacity of these vaccine candidates against the different stages of pneumococcal infection, including colonization, mucosal disease, and invasive disease in animal models is reviewed. Some of the human trials that have already been performed or that are currently ongoing are presented. Finally, the feasibility and the possible shortcomings of these candidates in relation to an ideal vaccine against pneumococcal infections are discussed.

Fig. 1

Commensal and pathogenic interactions of Streptococcus pneumoniae with human hosts. Commensal colonization of the upper respiratory tract occurs several times in life and is normally asymptomatic. The process triggers an inflammatory local response that is acute and controls the bacterial density and clearance. During the carrier state of the individual, transmission from hosts to hosts occurs (upper panel). Occasionally, the density of colonization may increase and pneumococci may invade mucosal sterile niches, such as the lungs and the middle ear, resulting in robust inflammatory responses at these locations. The development of pneumonia, sinusitis or otitis media are observed in these conditions (middle panel). The expression of virulence factors contribute for the evasion from the immune system. If the infection is not controlled, it may progress with the invasion of the bloodstream and other tissues by the bacteria, leading to more severe conditions such as bacteremia and meningitis (lower panel)

Fig. 2

Host–pathogen interactions during vaccine interventions. In non-vaccinated individuals, the three types of interaction may eventually occur (colonization, non-invasive disease, and invasive disease) (upper left panel). Polysaccharide (PS) vaccines induce low levels of systemic IgM against the antigens. These responses are more effective in adults but there is no memory response, leading to a temporary effect of the vaccine (middle left panel). Most of the protein vaccine candidates were shown to be immunogenic, inducing mucosal and systemic antibodies, as well as cellular immune responses, depending on the antigen, route of inoculation, and adjuvant used. The effectiveness of these vaccines against colonization and invasive diseases varies according to the antigen tested, and, usually, combinations of antigens tend to be more effective (lower left panel). PS-protein conjugate vaccines induce IgG against PS and are very effective against colonization and invasive diseases caused by pneumococcal vaccine-serotypes. The reduction in colonization opens a niche in the mucosa for other bacteria. As a result, an increase in diseases caused by pneumococcal non-vaccine serotypes and other respiratory pathogens is observed (upper right panel). The pneumococcal cellular vaccine (WCV) is a promising strategy that has been shown to induce T_H17 responses that are very effective against pneumococcal colonization. In addition, the induction of antibodies by this vaccine affords protection against invasive diseases. WCV was shown to induce protection against several pneumococcal serotypes in animal models. The elimination of pneumococcal colonization has to be carefully evaluated since colonization by other respiratory pathogens may emerge (middle right panel)