Vaccination against encapsulated bacteria in humans: paradoxes

Abstract

Infection with encapsulated bacteria can be prevented by vaccination with capsular polysaccharides, either plain or conjugated to a protein carrier. But results concerning these vaccinations raise several paradoxes. Polysaccharides from encapsulated bacteria are generally considered to be Tindependent antigens unable to trigger a T-dependent germinal center reaction, but strikingly, anti-polysaccharide antibodies are often mutated in humans. Polysaccharide-protein conjugate vaccines are able to induce a true T-dependent memory response with a rise in antibody titers and a switch to high affinity-IgG antibodies in children below 2 years of age, but neither the plain nor the conjugate vaccine can induce memory in older infants and adults. We propose some explanations to these paradoxes based on our recent observation that humans display a circulating splenic marginal zone B cell population with a pre-diversified immunoglobulin repertoire in charge of the immune response to T-independent vaccines. The impact of diseases generated by encapsulated bacteria has been underlined in many contexts and it is estimated that they are responsible for millions of children s deaths each year . Nevertheless, when looking at the abundant literature on immune responses to ' [1] encapsulated bacteria after vaccination by either plain or conjugated capsular polysaccharide vaccines, some paradoxes emerge which we would like to discuss. MESH Keywords Paradox 1It is generally accepted that bacterial capsular polysaccharides (CPS) are TI antigens that trigger specific B cells residing in the splenic marginal zone to secrete antibodies with opsonophagocytic properties against these bacteria . In rodents in which these responses have [2] been mostly studied, immunization do not induce an extensive proliferation within B cell follicles, neither the formation of germinal centers, and are for most of them taken care by unmutated germline antibodies . In humans on the contrary, the splenic marginal zone [3][4][5] contains B cells with mutated Ig receptors and mutated antibodies are raised in responses to encapsulated bacteria, these mutations [6][7][8] being responsible for the antibodies avidity for the immunizing antigen , . In all species, these TI responses do not trigger any [9 10] memory, the B cells engaged being able very rapidly to switch isotype and to secrete large amount of antibodies. These plasma cells can remain in the organism for various lengths of time, after which the response wanes out , . To account for the presence in humans of [11 12] mutated antibodies during a T-independent immune response that cannot normally trigger a cognate T-B dependent germinal center reaction, the classical explanation put forward by authors is that such responses are in fact taken care by memory B cells that bona fide have been primed by a previous encounter with the pathogen, either during an infection or by silent carriage . These memory B [13][14][15] cells would then eventually reside in the splenic marginal zone where they ...

Loss of Discrete Memory B Cell Subsets Is Associated with Impaired Immunization Responses in HIV-1 Infection and May Be a Risk Factor for Invasive Pneumococcal Disease

“…Ag-experienced CD19 ϩ CD27 ϩ memory B cells are divided into two main populations (15,16). Switched CD19 ϩ CD27 ϩ IgM Ϫ IgD Ϫ B cells are involved in T cell-dependent immune responses, secrete IgG and IgA Abs, and maintain long-term serological memory.…”

“…This cell population is believed to be the circulating counterparts of splenic marginal zone B cells and responds to the 23-valent polysaccharide pneumococcal vaccine (18). Unlike switched memory B cells, IgM memory B cells do not promote long-term protective humoral immune responses and it has been proposed that this B cell subset be regarded as natural effector B cells which bridge innate and adaptive immune responses (15). The ontogeny of IgM memory B cells in humans remains unclear; one suggestion is that this B cell subset may be derived from transitional B cells which are a naive B cell population that need the spleen to complete their development to mature B cells (19,20).…”

Les lymphocytes B IgM+IgD+CD27+chez l’homme

“…L'interpré-tation classique qui est faite est que ces anticorps sont produits par des cellules B mémoires ayant subi une activation antérieure dans les centres germinatifs. Notre proposition pour résoudre ce paradoxe est que ces anticorps soient produits par les cellules B de la zone marginale de la rate dont le répertoire est prédiversifié [20]. + , pourrait jouer un rôle particulier dans la physiologie de ces cellules.…”

“…Pour pallier ce problème, les vaccins dits « conjugués », tel le Prévenar (13-valent), ont été développés et impliquent un couplage des polysaccharides à des protéines vectrices, couplage qui permet d'induire une réponse T-dépendante classique chez le jeune enfant. Cependant, pour des raisons techniques (et de formulation), ce couplage difficile et très onéreux ne sera probablement pas possible pour un nombre plus élevé de sérotypes, ce qui à l'évidence limite la couverture vaccinale et risque d'augmenter la fréquence des infections dues à certains sérotypes non vaccinaux [20]. Or, nous avons montré que les cellules IgM + IgD + CD27 + étaient déjà présentes dans la zone marginale splénique et mutées avant l'âge de deux ans.…”

The role of complement in the success of vaccination with conjugated vs. unconjugated polysaccharide antigen

“…The fact that primary complement deficiency predisposes to infection with micro-organisms with a complex polysaccharide capsule seems to suggest this and casts doubt on the use of polysaccharide-type vaccines in these patients [63]. Complement deficiencies are rare [64], and few studies investigate the impact of these deficiencies on vaccine success.…”