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Is it theoretically possible to generate a vaccine that is more effective at inducing protective immunity than the infection itself?

Immunity as evolutionary contest between pathogen and hostThe ecological interaction between infectious pathogen and host is one where the pathogens evolutionary goal is continued reproduction. Many infections result in complete elimination of pathogen with subsequent lifelong immunity against reinfection. Evolutionary considerations may suggest that natural immunity has been optimized over long periods and artificial vaccines are likely to be inferior. The second category includes diseases and vaccines under consideration in this essay, namely those in which the immune system is either unable to fully eliminate primary infection or is unable to prevent subsequent reinfection of the same species of infectious agent through immunological memory. This limitation of protective immunity allows a theoretical possibility of designing a vaccine to provide greater efficacy at inducing protective immunity than natural infection.

Epidemiological evidence

Assessing natural immunity compared to vaccine-mediated immunity is by no means simple. Aside from challenge experiments, which are an ethical quagmire, the next best estimates would come from epidemiological surveys. True estimates would require large samples including adequate unvaccinated cases, problematic for diseases with widespread vaccine coverage, in order to pick up rare cases of actual infection. Further, detailed lifelong histories together with laboratory confirmed status of past infection (including ideally molecular typing and serological correlates) would be necessary to compare against vaccination histories, if possible along with exposure histories. For many diseases, based on limited evidence, there is a widespread understanding that natural immunity is better than vaccine-mediated immunity (1,2). Unfortunately this is dependent on surveillance for repeat infections, which is of a different quality in the pre-vaccination era compared to the present.Tetanus may provide the strongest example for the possibility of better vaccine-mediated immunity than natural immunity using epidemiological evidence, while comparing to a well-described example of where natural immunity is usually said to be better than vaccine-mediated immunity, namely varicella. For tetanus, received wisdom is that infection does not confer immunity (3) . Series of repeated infections have been reported (4). Irreversible binding and rapid sequestration of the tetanus toxin tetanospasmin into neurons may be responsible for the short exposure of the toxin to the immune system and thus minimizing time for generation of an adaptive immune response. Together with the small doses required for a severe, often fatal clinical course, few people develop antibodies, as serosurveys in non-immunized populations have shown (5). In contrast, the formaldehyde treated tetanus toxoid has a virtually 100% seroconversion rate, and while [e]fficacy of the toxoid has never been studied in a vaccine trial. It can be inferred from protective antitoxin levels that a complete tetanus toxoid series has a clinical efficacy of virtually 100%(6) . Reasons for higher vaccine-mediated than natural immunity in this case may include a higher dose of antigen in the vaccine and a longer period of time in the bloodstream for generation of an adaptive immune response.

In contrast, taking varicella as typical of many other diseases where natural immunity is taken to be superior to vaccine-mediated immunity, clinical chickenpox after reinfection is considered extremely rare. There are only a handful of case reports with serological correlates (7,8). Considering the historically widespread risk, this, together with an upper estimate of a 7% attack rate in an outbreak setting for children with a clinical history of previous varicella (9), itself prone to misreporting, demonstrates the very high rate of natural immunity. In contrast, clinical efficacy of the varicella vaccine has been reported in a meta-analysis at 84.5% (95% CI 44-100%) and vaccine failures are constantly reported (10). As these contrasting examples may show, evaluating natural vs vaccine-mediated immunity from epidemiologic evidence alone is not without problems. However, they also demonstrate that there does exist the possibility that vaccines can lead to better immunity than natural infection. Host-pathogen interaction with compromised immunity

Having discussed epidemiologic evidence, the rest of the essay will concentrate on potential areas of impaired host immune response to pathogen where there is at least a theoretical possibility of a vaccine performing better than natural infection in protecting the host from clinical infection. Broadly, immune evasion will be discussed in terms of a) host immune pathways evaded, b) host life stage-dependent immune status, and c) vector and life-cycle issues. Aspects of vaccine formulation will be covered, including quantity, specificity and presentation of antigen, the use of adjuvants to enhance immune response, and the route of vaccine delivery. Also, examples from all three classes of infections in which compromised immunity is prominent will be used, namely multiple repeated infections, chronic infections, and infections cycles with latent and reactivation phases.

Evasion of host immune pathways

Minimizing inflammationHuman papillomavirus is typical of viruses that evades the immune system through avoiding exposure to the bloodstream, reproducing in the epithelium without causing inflammation so avoiding detection. Vaccines can induce better protective immunity as administration is intramuscular thus in a context permissive to immune recognition, virus-like particles (VLPs) have capsids exposed to the immune system, VLPs are able to elicit high titres of neutralizing antibodies (two orders of magnitude more than natural infection), and antigen dose exceeds that in natural infection(11). Th1 vs Th2 responsesOne classic example of a pathogen biasing the TH1:TH2 response ratio is in leishmaniasis, where diffuse cutaneous leishmaniasis is one manifestation of a bias to a CD4 (Th2) dominated response with a lack of efficient CD8-mediated (Th1) killing of parasites. Protective immunity is thus limited in this more chronic form of infection. Attempts have been made to induce a Th1 bias in the response when using vaccine approaches, including live attenuated, killed and antigen-based methods, by utilising BCG as an adjuvant to enhance CD8 (ie TH1) response(12). In this case, such a Th1 bias can lead to better protective immunity than natural infection, within the constraints of the model used.

Antigen variation Influenza virus uses antigenic shift and antigenic drift to evade host immune response, allowing for repeated infections(13). To avoid lack of immune memory, or confounding effects of original antigenic sin, one strategy is to use conserved epitopes of the influenza virus to generate a universal vaccine (14). Immune privilege

In chronic infections, and those with a period of latency, pathogens may enter immune-privileged sites to reduce host immune response. Varicella zoster virus (VZV) after primary infection as varicella enters dorsal nerve root ganglia and is latent, reactivating sporadically as herpes zoster. During the period of central nervous system (CNS) latency, minimal protective immunity is elicited due to immune privilege. By introducing high antigen loads into the bloodstream with zoster vaccination, the immune system is stimulated above the level of natural infection to generate protective immunity against the latent VSV (15). Another example of relative immune privilege is the liver (16) . Plasmodia have a liver stage where they are relatively protected from the immune system. Vaccine strategies have included using liver stage antigen 1 (LSA-1), the only P. falciparum antigen expressed exclusively by hepatocytes in vaccination strategies by presenting it outside the tolerogenic environment of the liver in order to stimulate the immune system into acting against liver-stage parasites, over and above the level of protective immunity generated by natural infection (17). Granuloma formationOrganisms may subvert natural protective immunity through stimulating immunopathologic responses that serve to evade host defences. Granuloma formation by pathogens in the Mycobacterium tuberculosis (Mtb) complex demonstrates this. Upon initial infection, inflammatory reaction often leads to a granuloma containing dormant mycobacteria that are inaccessible to elimination by the immune system(18). It can be conceived that vaccines leading to sterile eradication of Mtb can be designed, that overcome the suboptimal natural immunity leading to latent infection. Kaufmann suggests a vaccine strategy of stimulating different T cell populations that can in concert eliminate latent Mtb: chemoattractant Th17 cells, Th1 cells that activate macrophages, cytotoxic CD8 T cells that attack intracellular Mtb, and antibodies to opsonize released Mtb(19). Host life stage-dependent immune statusRelative infantile immunodeficiencyA few infections are prominent in neonates and infants, among them Haemophilus influenzae type B (Hib) which is encapsulated and for which immunity is dependent on a thymus-independent polysaccharide antigen (20). Under 2 years of age, the immune system is not sufficiently matured to naturally resist invasive infection by Hib, thus causing high rates of morbidity and mortality in this age group (21). The recent use of a conjugated vaccine (with diphtheria or tetanus toxoid) enhances immunogenicity in this age group over that of natural infection leading to protection against invasive disease (22). Immunosenescence

Immunosenescence constitutes a major deficiency of natural protective immunity against infectious disease. In the older adult, a whole array of changes to innate and adaptive immune mechanisms contribute to a poorer protective response than in younger adults. Work on this phenomenon in the context of influenza has been active, with demonstrable poor cellular immunity to natural infection in the elderly (23). While current influenza vaccination strategies in the elderly remain suboptimal (24), there is the potential to improve these potentially over the response to natural infection by modulating the immunosenescent phenotype: Cell-intrinsic changes that impair the activation and differentiation of T cells and B cells are rather subtle and may be overcome by temporally limited interventions at the time of vaccination. (25). Pathogen-vector and life-cycle influencesVector-associated immunomodulation

Apart from the pathogen itself, the arthropod vector may also contribute to evading host immune protection. Classically, sandfly saliva inoculated transcutaneously during transmission of Leishmania parasites increase infectivity (26) by modulating host immune response including downregulation of TH1 and suppression of TNF- (27). Vaccines have been tested which incorporate immunogenic salivary antigens, enhancing protective immunity over and above that of natural infection(28) .Tissue-specific life-stagesSchistosomes infect humans via the skin as cercarial larvae, transiting through the skin as schistosomlae before maturing to adult worms with associated immunopathology. Repeated infections are common, which indicates that adaptive immunity against larval forms is not effective. One mechanism by which cercariae avoid stimulating the immune system is by secretion of immune modulators including prostaglandins which inhibit antigen-presentation by Langerhans cells in the skin (29). The increased efficacy of irradiated cercariae in inducing protective immune in mouse models(30) demonstrates how artificial vaccine formulations focusing on particular parasite life-stages may improve on natural immunity. ConclusionThis essays aims to demonstrate that not only is it theoretically possible but, given definitional constraints, that vaccine-mediated immunity has already surpassed natural immunity in a few cases by epidemiologic and immunologic criteria. Both clinical endpoints and immune correlates such as seroconversion have been used in the discussion. Further theoretical extensions to the principle have been proposed within a typology of compromised natural immune responses and suggestions of potential vaccine strategies made. References1. Frequently Asked Questions - Vaccination - Ministre de la Sant et des Services sociaux [Internet]. [cited 2014 Mar 30]. Available from: https://www.msss.gouv.qc.ca/sujets/santepub/vaccination/index.php?foire_aux_questions_en#q14

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