What do the next 100 years hold for pneumococcal vaccination?

Keywords::

• conjugate vaccine
• meningitis
• personalized vaccination
• pneumococcus
• pneumonia
• polysaccharide
• risk groups
• serotype replacement

Babies are born with a fully functional immune system with one obvious exception: the ability to mount an antibody response to polysaccharide-encapsulated bacteria [1]. This ability matures slowly during the first 18–24 months of life. Why would that be? Why would babies be born with such an obvious transient immunodeficiency and therefore susceptible to pneumococcal infections? The clue may be that this vulnerability allows the mucosa of the upper respiratory tract to become colonized with pneumococci, the most important representative of the encapsulated bacteria. The price of colonization would generally be a mild but sometimes recurrent otitis media, the (much greater) benefit would be that other pathogens such as Staphylococcus aureus are unable to reach the ideal breeding ground of the nasopharynx.

From a personal as well as a public health perspective, which differs from the evolutionary, population-based perspective, a higher price is paid for mucosal colonization by pneumococci. Pneumococcal pneumonia, bacteremia and meningitis are severe systemic diseases that may occur when mucosal barrier functions are inadequate. For these reasons the infant immune system should be able to respond to encapsulated bacteria and, in order to prevent invasive infections, be boosted by vaccination against pneumococci.

It is difficult to precisely date the first successful vaccination against pneumococcal disease, but the experiments performed by Sir Almroth Wright in South Africa in 1911–1913 would probably qualify [2]. Wright, who at that time had a name in typhoid vaccination, was called upon because over 10% of the native African labor force in the diamond mines of Witwatersrand (South Africa) suffered from pneumonia within 3 months of deployment. Through vaccination, Wright was able to successfully reduce the incidence of pneumonia by more than 50%. The vaccine consisted of dried, heat-inactivated sputum from pneumonia patients. In the discussion of his 1914 paper in The Lancet, Wright wrote “we have here to deal with the immunotherapy of pneumococcus infections, and in particular with the employment of vaccines in the prophylaxis and treatment of pneumonia” [2].

The pneumococcus protects itself from immune system-mediated attack via the formation of a thick polysaccharide capsule. As an extra defense against the immune system, pneumococci use a total of 92 structural and antigenically different polysaccharides that are organized into serogroups and serotypes [3,4]. Clinical protection against invasive pneumococcal disease is conferred by type-specific antibodies directed against the capsular polysaccharide. Cross-protection only occurs within a serogroup (e.g., serotype 6A and 6B) but not across serotypes. Along with polysaccharide, the capsule of pneumococci also contains a number of proteins, such as pneumolysin (Ply), pneumococcal surface protein A (PsPA) and pneumococcal surface protein C (PspC). These proteins do not vary across serotypes and, therefore, could be ideal vaccine candidates. Although promising results have been obtained, it remains to be seen whether large-scale application of protein-based pneumococcal vaccines would be effective in the long run [5,6]. Nonencapsulated pneumococci are avirulent but the colonization profile of triple-knockout pneumococci (Ply^-/-, PspA^-/-, PspC^-/-) turned out to be almost identical to that of wild-type pneumococci [7]. It appears that other virulence genes can compensate for these capsular proteins, leaving the polysaccharide as the major vaccine target.

The first pneumococcal vaccines were composed of the purified capsular polysaccharides of prevalent serotypes. The current polysaccharide vaccine is composed of the capsular polysaccharides of the 23 most prevalent serotypes, which are accountable for approximately 90% of all pneumococcal infections [8,9]. This polysaccharide vaccine is preventing invasive pneumococcal disease in both children over 5 years of age and adults [10]. An obvious drawback of a polysaccharide vaccine is that it does not confer protection in the age-groups most at risk for invasive pneumococcal disease: infants and young children [11]. In addition, protection in the elderly is far from complete [12,13]. The reason for failure of a polysaccharide vaccine in infants is obvious: an unresponsive immune system cannot generate protective immunity. Polysaccharide-specific B lymphocytes, in order to become activated to produce antibodies, require specific recognition via the antigen receptor and costimulation via complement receptor type 2 (CR2) [14]. This costimulation is accomplished because the polysaccharide molecule activates complement component C3, which splits to produce C3d. C3d then deposits onto the polysaccharide molecule and serves as the ligand for CR2 [15]. Neonatal B lymphocytes express little or no CR2 and, consequently, the required costimulation fails [14,16].

When vaccine and vaccinee are not compatible, the only option is to improve the vaccine. A breakthrough discovery, believed by many to be of Nobel prize-winning magnitude, was made by Oswald Avery and Walther Goebel, who found that covalent coupling of a protein to a polysaccharide antigen changed the nature of the immune response to the polysaccharide [17]. Conjugation of protein to polysaccharide solved the two major drawbacks associated with a polysaccharide vaccine: induction of immunological memory and antibody responsiveness in infants. The discovery by Avery and Goebel may have been made at the right place (the Rockefeller Institute, NY, USA) but certainly at the wrong time (1929). During that period it was not fashionable to study prevention of infectious disease because it was believed that antibiotics would make such studies obsolete. It therefore took almost 50 years before the principles of Avery were rediscovered and polysaccharide conjugate vaccines were prepared. A conjugate vaccine of Haemophilus influenzae type b polysaccharide was developed in the late 1980s and has lead to the virtual disappearance of invasive Haemophilus influenzae type b disease in all countries in which the vaccine is used [18,19]. Subsequently, and following the same principles, pneumococcal conjugate vaccines were developed, which consist of a mixture of polysaccharide conjugates of the top seven pneumococcal serotypes causing otitis media in children from the USA (serotypes 4, 6B, 9V, 14, 18C, 19F and 23F) [20]. These vaccines turned out to be very effective in preventing vaccine-type invasive pneumococcal infections in infants and young children [21,22]. The top seven pneumococcal serotypes differ for every age group, for every pneumococcal disease or for every geographical region in the world, and therefore coverage of the heptavalent pneumococcal conjugate vaccine differs.

Since the introduction of smallpox vaccination by Sir Edward Jenner in 1796, it took 184 years until the WHO could declare the world free of smallpox [23]. How long will it take to eliminate pneumococcus from the world?

At least three major, scientific challenges lie ahead. First, serotype replacement on mucosal surfaces, resulting in replacement disease. After large-scale introduction of the heptavalent pneumococcal conjugate vaccine, including serotype 19F, serotype 19A became the primary cause of pneumococcal pneumonia [24,25]. This came as a total surprise because, up to that moment, the prevailing paradigm was that serotypes within one serogroup would confer cross-protection. Indeed, the previously indicated and generally accepted figure of 90% coverage of the 23-valent polysaccharide vaccine has a built-in 15% cross-protection. Furthermore, prior to introduction of the heptavalent pneumococcal conjugate in the USA, serotype 19A was not on position number eight in the pneumococcal rank-order; it held position number 18 [26]. Owing to the replacement disease, recently released 11- and 13-valent conjugate vaccines have now incorporated a 19A conjugate [27–29].

But what will happen after large-scale introduction of 11- and 13-valent conjugate vaccines [30–32]? Will other serotypes continue to cause replacement diseases, until all 91 serotypes have had their moment of glory? Maybe the solution could be to design vaccines that do not interfere with mucosal colonization, but only prevent invasion. Identification of the genes that determine invasiveness is an important first step to reach this goal.

The second challenge is the optimization of protection in other vulnerable risk groups. These include the elderly and a variety of conditions associated with impaired immunity such as splenectomy [33–35], malignancy [36,37], stem cell transplantation [38] and specific defects [39]. Whether the pneumococcal conjugate vaccines will be clinically effective in preventing community-acquired pneumonia in the elderly is currently being investigated in ongoing studies [40]. Currently, we have one size (of vaccine formulation or, at best, some formulations) that should fit all (vaccinees). However, genetic polymorphisms of innate immunity genes (such as for the Fcγ receptor IIa [41]) determine not only the magnitude but also the direction of the response to the vaccine [42,43]. Personalized vaccination strategies that take into account these polymorphisms and employ tailored adjuvants could be the way to circumvent these hurdles and lead the way to even more effective pneumococcal vaccines for those at special risk [44,45].

The third and maybe most important challenge is more politically than scientifically based: to make efficient vaccines available globally [46].

Before we can eliminate pneumococcal disease from the world and protect vunerable populations of society from virulent colonization these scientific challenges must be met.

Acknowledgements

The authors would like to thank their colleague Bart Vlaminckx who kindly served as a sparring partner for their ideas.

Financial & competing interests disclosure

Ger T Rijkers received consulting fees and travel grants from Wyeth/Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.