There are many instances in which natural infection with a particular virus will elicit essentially life-long immunity whereas infection with a closely related live attenuated vaccine strain of the same virus will not provide sufficient levels of immunity to confer long-term protection Table 1.
What is the difference between natural infection vs. Most likely the differences are related to the need for vaccine safety. Most live, attenuated vaccines have been selected on the basis that they replicate less efficiently in their intended host, resulting in reduced pathogenicity and an improved safety profile. However, if the vaccine strain replicates less efficiently and is cleared more rapidly, then the overall antigenic load will be reduced and this is likely to impact the magnitude of the ensuing antiviral immune response Figure 2.
At early time points after vaccination, immunity may reside above the threshold of protection but if it is at or near the protective level, then it could decline to below the protective threshold by the time it reaches the plateau phase. This may explain why vaccines as divergent as the non-replicating, acellular pertussis vaccine [ 6 — 8 ] and the live, attenuated varicella vaccine [ 57 ] both initially provide protective immunity that fades over a relatively short period of time.
Booster vaccination may further increase the levels of immunity in the short-term e. Natural acute viral infection, on the other hand, often elicits a higher level of immunity that is more likely to plateau above the protective threshold after a single infection and thereby maintain long-term immunity as well as long-term protection Figure 2. During longitudinal analysis of 45 subjects followed for up to 26 years Mean: Similar results have been found in other studies involving vaccination against rubella [ 67 ] or yellow fever [ 59 ] in which a biphasic response occurs after vaccination or infection.
Although representing only anecdotal evidence, when we examined the plateau phase of long-term antibody responses to measles, mumps, or rubella in a small cohort of vaccinated subjects [ 11 ]; Supplemental Appendix , the antibody responses appeared to be as durable as that observed following natural infection with these viruses. However, similar to previous studies on measles [ 68 ] and mumps [ 69 ], the set point level of the plateau was lower following vaccination than after natural infection, and resided nearer to the putative threshold required for protective immunity.
In other words, following vaccination or infection, detectable antigen-specific immunity may be long-lived, but if it is not maintained above the protective threshold then protective immunity itself may not be long-lived. This may explain the dichotomy between durable protection mediated by natural viral infection and the lack of long-lived durable protection following a single infection with attenuated vaccine strains of the same virus Table 1. In this illustration, natural infection with a wild-type virus e. Following infection with a live, attenuated vaccine e.
Following booster vaccination, antiviral immunity is increased and if the set point of the new plateau phase resides above the seroprotective threshold, then long-term immunity as well as long-term protection is maintained. Vaccines have provided many success stories and even a requirement for a single booster vaccination is a small price to pay for durable immunity without necessitating severe or potentially life-threatening disease from natural infection.
However, some vaccines are only partially effective even after multiple vaccinations e. One way to improve vaccines is to compare successful vaccines and identify potential factors that may be involved with determining long-term vaccine efficacy. In broad terms, vaccines can be categorized into three general classes: According to the imprinted lifespan model for induction of long-lived plasma cells [ 22 ], stimulation of T cell-independent antibody responses will be relatively short-lived without T cell help.
Although monovalent protein antigens will elicit better, more durable antibody responses due to acquisition of T cell help , the most long-lived antibody responses are predicted to occur when a multivalent antigen triggers strong B cell activation as well as effective T cell help. A putative multivalent protein antigen is shown in comparison to a monovalent protein or non-protein antigen.
In this example, B cell clones extract antigen from follicular dendritic cells FDC , followed by processing protein antigens only and presentation to T follicular helper T FH cells. Several lines of evidence indicate that multivalent interactions increase B cell receptor BCR clustering and improve the ability of B cells to secure antigen from antigen presenting cells [ 88 — 90 , 93 — 95 ]. Although more studies are needed, the combination of increased BCR clustering and increased antigen presentation to T FH cells by multivalent proteins may play a role in imprinting an increased plasma cell lifespan and sustained antibody production.
This T-independent antibody response provides only a limited duration of protection in elderly subjects [ 70 ] and antibody responses decline to baseline levels within 3—5 years after vaccination [ 71 ]. Moreover, T-independent antibody responses fail to establish memory and re-vaccination with purified polysaccharides have been found to lower serum antibody responses, and decrease the frequency of antigen-specific memory B cells [ 72 ]. To overcome these limitations, newer polysaccharide vaccines such as Prevnar are conjugated to a carrier protein e.
T cell contact and the additional costimulation from these interactions elicits stronger and more durable antibody responses than that observed with T-independent antigens such as non-conjugated polysaccharide vaccines. Tetanus and diphtheria toxoid vaccination induce intermediate to long-lived antibody responses that decline with an year and year half-life, respectively [ 11 ] and although adult booster vaccination is currently recommended every 10 years in the United States, other countries such as the United Kingdom no longer recommend adult booster vaccination [ 73 ] due to the observation of long-lived vaccine-mediated protection in the absence of further immunization.
One reason for this is that the duration of protection is a function of the magnitude of the antibody response as well as the half-life of the antibody response and if neutralizing antibody levels begin at a high level, then long-term protective immunity may be maintained potentially for decades even with an year antibody half-life Slifka, manuscript in preparation. Unlike monovalent vaccine antigens such as tetanus and diphtheria that require a 3- to 5-dose primary vaccination regimen in order to achieve long-term protective immunity, multivalent vaccine antigens and many natural acute viral infections elicit long-term immunity after only one or two antigenic exposures.
Measles vaccination is likely to induce the same immunological signaling interactions since it represents a closely related live paramyxovirus infection.
However, with the milder infection and reduced antigen load associated with vaccination vs. A recent study examining the duration of antibody responses following 1, 2, or 3 doses of Cervarix, a highly repetitive non-infectious virus-like particle vaccine against human papilloma virus HPV , is also particularly informative [ 76 ]. In this study, subjects were followed for up to 4 years after primary vaccination and the data shows that a single immunization induces a biphasic response that peaked at the 1 month time point, declined sharply by the 12 month time point, but then showed a stable plateau phase of prolonged antibody production from 1 to 4 years after vaccination that was higher than that observed after natural HPV infection.
This shows that a single vaccination with an optimized multivalent protein antigen is capable of eliciting persistent antibody responses. A 2-dose or 3-dose vaccination schedule resulted in about a 5-fold higher antibody level during the plateau phase compared to the 1-dose schedule but the durability of the long-term antibody response was notably similar.
A recent report has also now shown that a two-dose schedule of Gardasil is non-inferior to the 3-dose schedule [ 77 ] and more studies are needed to determine if the levels of serological immunity following a single dose of HPV vaccine might be sufficient to provide long-term homologous and heterologous protection. If this is observed, then it could have important implications in the vaccination of vulnerable populations in developing countries with a high burden of HPV-associated disease.
One of the most intriguing questions regarding human vaccination is why certain vaccine antigens induce robust lifelong antibody responses, while protective immunity to other antigens fades with time. As discussed earlier, we found that humoral immunity to viruses tends to be long-lived, while immunity to non-repetitive protein antigens declines more quickly [ 11 ].
For example, long-term antibody responses to measles, mumps, and rubella demonstrated no significant decline in antibody when followed longitudinally for up to 26 years. Other studies examining the duration of antibody to measles in addition to mumps and rubella also indicated essentially lifelong immunity when extrapolated from antibody titers measured longitudinally for up to 2 years after sustained peripheral B cell depletion by anti-CD20 treatment in rheumatoid arthritis patients [ 78 ]. By comparison, antibody responses to tetanus and diphtheria show more rapid decay rates, with average half-lives in the range of 11—19 years [ 11 ].
These broad differences in antibody maintenance patterns indicate that antigen-specific plasma cell populations can have distinct lifespans. Since terminally differentiated plasma cells show little to no expression of surface immunoglobulin, MHC Class II molecules or other key B cell signaling receptors [ 79 , 80 ], it is likely that the lifespan decision is made prior to differentiation into a plasma cell. According to the imprinted lifespan model, those B cells capable of binding antigen through the BCR and presenting to T cells will receive additional signals to allow recruitment into the long-lived plasma cell pool with multivalent protein antigens providing a survival advantage over monovalent protein antigens Figure 3.
In practice, there appear to be some exceptions to this rule.
For instance, the RTS, S malaria vaccine is comprised of a repetitive, particulate antigen coupled with a strong adjuvant [ 81 ] and based on the imprinted lifespan model this should elicit long-term immunity. This could mean that not all highly repetitive particulate antigens induce long-term immunity or it is possible that this vaccine induces a biphasic antibody response in which the early antibody response resides above a protective threshold but then declines to below the protective threshold at later time points.
This would not be surprising and would mimic the results obtained following MMR vaccination in which immunity can be long-lived, but booster vaccinations are needed to elicit antiviral antibody responses that are maintained above a protective threshold. Alternatively, the protective threshold may be relatively high since this is a subunit vaccine against a single P. Although longitudinal analysis of antigen-specific serum antibody responses supports the position that different vaccine classes can induce distinct patterns of antibody maintenance [ 11 , 12 , 78 ], the cellular mechanisms that underlie these differences are less well defined.
The germinal center GC reaction is believed to be the central point for antigen-specific B cell fate selection. The GC is a transient structure that forms within B cell zones of lymphoid tissues following antigenic exposure, either through natural infection or immunization, with the first description of this structure dating back more than a century [ 83 ].
Based on this segregation, a general model of the GC reaction developed, wherein the DZ represents a region dedicated to antibody diversification achieved through proliferation and SHM of the immunoglobulin variable genes. The B cell clones able to successfully compete are recruited into the memory pool either long-lived plasma cells or memory B cells , while those unable to compete effectively are deleted through apoptosis. In this way, only high affinity B cell clones are selected for subsequent memory responses.
Recent advances in the ability to visualize different cell populations and track antigen in situ have expanded this standard model, adding important detail regarding the selection and cycling of B cells during this process [ 83 ]. Since activated B cell clones compete for interactions with T FH cells, we speculate that these interactions may be key to imprinting plasma cells with different lifespans and multivalent or aggregated antigens may offer a competitive advantage in this regard. It is well established that soluble monomeric proteins are poorly immunogenic but chemical or heat-induced aggregation greatly increases immunogenicity [ 86 ].
This indicates that particulate antigens e. I n vitro studies, using chimeric BCR constructs specific for different antigens have demonstrated that the quality of the BCR-antigen complex also has a substantial impact on the ability of B cell clones to present antigen and interact with cognate T cells [ 88 ].
B cell clones with higher affinity for antigen are able to better maintain the BCR-antigen complex, resulting in more efficient peptide presentation, and likely better competition for limited T cell help in addition to potentially more prolonged T cell: Immunoelectron microscopy studies support this model, demonstrating that antigen remains bound to the BCR following internalization and transport to the MHC Class II peptide-loading compartment, and this process is separate from the much less efficient uptake of antigen through pinocytosis [ 89 ].
Multimeric proteins with repetitive B cell epitopes will be bound by multiple BCR and the resulting avidity of these interactions is expected to be stronger than that observed with the affinity of a single BCR binding to a single epitope on a monovalent protein. Bearing this in mind, particulate multivalent antigen presented on microbeads is up to fold more effective at triggering B cell uptake and peptide presentation to T cells than soluble antigen [ 90 ]. Successful vaccines have changed modern medicine by reducing the morbidity and mortality associated with many infectious diseases.
Despite these successes, some vaccines require improvement e. Analysis of vaccine efficacy and the duration of protective immunity are beginning to provide new details on the mechanisms underlying long-term immunity and several trends are beginning to emerge. In the absence of T cell help, polysaccharide vaccines elicit only short-lived immunity and no immunological memory.
In contrast, T cell-dependent protein antigens elicit long-lived immunity but most vaccines require booster vaccination in order to raise the plateau level of long-term immunity above a protective threshold. More studies are needed to determine how these interactions can be optimized to induce long-lived protective immunity with the fewest number of vaccinations and further analysis of the mechanisms underlying successful vaccines will be important for improving future vaccine design.
This potential individual and institutional conflict of interest has been reviewed and managed by OHSU.
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See other articles in PMC that cite the published article. Abstract Vaccines represent one of the most compelling examples of how biomedical research has improved society by saving lives and dramatically reducing the burden of infectious disease. Vaccination, Immunological Memory, Antibody, Protection. Success of current vaccines It is difficult to over-emphasize the role that vaccines have played in public health by controlling infectious disease, improving the quality of life and increasing life expectancy. Open in a separate window. Vaccination reduces the incidence of infectious disease Values represent the number of annual cases of disease that occurred in the United States during the pre-vaccine era adapted from [ 2 ] compared to the number of cases for each disease reported to the CDC in [ 3 ].
Duration of immunity depends on the characteristics of the vaccine or infection Studies describing the duration of immunological memory following acute viral infection date back to the time of Panum, who in , reported that the maintenance of long-term immunity against measles could be sustained for up to 65 years in the absence of re-exposure to the pathogen [ 10 ]. Role of adjuvants in determining the magnitude and duration of immunity Adjuvants have been used extensively in clinical settings to enhance the efficacy of inactivated or recombinant vaccine antigens [ 43 — 45 ].
All vaccines require boosters One of the most common misconceptions in vaccinology is that inactivated vaccines and subunit vaccines are weaker immunogens and will require booster vaccination whereas live, attenuated vaccines are expected to elicit the same degree of durable protection as that achieved by natural infection.
Table 1 Artificially attenuated virus vaccines requiring booster vaccination. The duration of immunity does not necessarily equate to the duration of protection There are many instances in which natural infection with a particular virus will elicit essentially life-long immunity whereas infection with a closely related live attenuated vaccine strain of the same virus will not provide sufficient levels of immunity to confer long-term protection Table 1. Relationship between long-term immunity and long-term protection In this illustration, natural infection with a wild-type virus e.
Lessons from vaccines that elicit immunity of differing duration Vaccines have provided many success stories and even a requirement for a single booster vaccination is a small price to pay for durable immunity without necessitating severe or potentially life-threatening disease from natural infection.
Characteristics of a vaccine antigen determine subsequent levels and duration of immunity A putative multivalent protein antigen is shown in comparison to a monovalent protein or non-protein antigen. Potential mechanisms underlying the development of durable humoral immune responses One of the most intriguing questions regarding human vaccination is why certain vaccine antigens induce robust lifelong antibody responses, while protective immunity to other antigens fades with time.
Footnotes This potential individual and institutional conflict of interest has been reviewed and managed by OHSU.
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