Wanted, dead or alive: new viral vaccines

Abstract

Vaccination is one of the most effective methods used for protecting the public against infectious disease. Vaccines can be segregated into two general categories: replicating vaccines (i.e., live, attenuated vaccines) and non-replicating vaccines (e.g., inactivated or subunit vaccines). It has been assumed that live attenuated vaccines are superior to non-replicating vaccines in terms of the quality of the antiviral immune response, the level of protective immunity, and the duration of protective immunity. Although this a prevalent viewpoint within the field, there are several exceptions to the rule. Here, we will explore the historical literature in which some of these conclusions have been based, including "Experiments of Nature" and describe examples of the efficacy of replicating vaccines compared to their non-replicating counterparts. By building a better understanding of how successful vaccines work, we hope to develop better "next-generation" vaccines as well as new vaccines against HIV--a pathogen of global importance for which no licensed vaccine currently exists.

Figure 1

Evolution of Vaccines. Prior to the introduction of vaccines, immunity developed following natural infection with a specific viral pathogen. Live attenuated vaccines often are developed from the wild-type pathogen after selecting for less virulent strains that are able to infect the host and elicit antiviral immunity, but with greatly reduced disease severity. In cases in which live attenuated vaccines have rare but serious adverse events, further refinement of the vaccine is provided by developing an inactivated formulation for immunization. This may consist of a whole virus vaccine that has been inactivated by formaldehyde (e.g., IPV), use of a non-replicating strain of virus (e.g., MVA), or replacement with a subunit vaccine consisting of only one or a few protective antigens (e.g., Hepatitis B surface antigen). The risk of morbidity or mortality is reduced as the immunogenic insult is modified from natural infection to attenuated infection, to immunization with an inactivated or non-replicating antigen. In some cases, such as in the development of the Hepatitis B vaccine, the intermediate step involving the development of an attenuated vaccine may be omitted if a non-replicating vaccine provides effective immunity. Abbreviations: OPV; live oral polio vaccine, IPV; inactivated polio vaccine, MVA; Modified Vaccinia Ankura

Figure 2

Relative contributions of humoral and cellular immunity during primary or secondary infection. During primary viral infection, antiviral T cell responses are critical for reducing viral replication in addition to contributing to the development of an effective antibody response. Primary T cell-dependent antibody responses are mounted during the course of infection and take time to undergo immunoglobulin class-switching and somatic hypermutation as they provide assistance to virus-specific T cells in resolving the infection. Following recovery from primary infection (or vaccination), persisting virus-specific antibody represents the first line of defense against secondary infection. If secondary infection does occur, then circulating antibodies and presumably memory B cells that proliferate and differentiate into antibody secreting cells will reduce virus dissemination and allow time for the development of an antiviral T cell response. Memory B cells are highly efficient at presenting specific antigen (Lanzavecchia, 1985) and therefore may also be involved with more rapid and efficient presentation to T cells as well. Pre-existing T cell memory will also play a role in protection against secondary infection. However, even if T cell memory has declined or is lost, the long-term maintenance of antiviral antibody responses will suppress virus replication until a new virus-specific T cell response is mounted from the naïve repertoire.