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Partis , Richard A. Mueller , Francis J. Chrest and Antonino Passaniti. Barr and Adriano Fontana. Special Lecture Special Lecture. Clinical Investigations Clinical Investigations. Grady , Richard S. Paules and Gretchen H. Yandell , Karl T. Kelsey and Howard L. Lippman , Dong M. Jack Lee , John G. Batsakis , Reuben Lotan , Michael A. Tainsky , Walter N. Hittelman and Waun Ki Hong. Walker , Wei Duan , Emil A.
Popovic , Andrew H. Kaye , Frank H. Tomlinson and Martin Lavin. Molecular and Cytogenetic Analysis. Knight , Pamela J. Fong , Paul V. Zimmerman and Peter J. Panos Papadopoulos , Susan A. Ridge , Catherine A. Boucher , Carol Stocking and Leanne M. A Breast Cancer Study. Labrecque , Diana M. Barnes , Ian S. Fentiman and Beverly E. Articles Advances in Brief. Instead, this work indicates that the duration of serum antibody responses may not only differ between pathogens e.
This suggests that there are antigen-specific characteristics that influence the magnitude and durability of the antibody response to each particular antigen. An effective HIV vaccine will most likely need to elicit high affinity, broadly neutralizing antibodies with substantial somatic hypermutation [ 17 , 18 ] and unlocking the secret s to long-term maintenance of these types of immune responses will be key to the success of a protective HIV vaccine.
Moreover, a better understanding of the underlying mechanisms responsible for inducing long-lived antibody responses will be important for improving other suboptimal vaccines e.
Several models have been proposed to explain the mechanisms underlying the durability of serum antibody responses, including the polyclonal stimulation model, the plasma cell niche competition model, and the plasma cell imprinted lifespan model [ 19 — 21 ], reviewed in [ 22 ]. According to the polyclonal stimulation model, successive rounds of infection or vaccination will induce polyclonal B cell activation that results in repopulation of the pre-existing plasma cell pool and increased antigen-specific antibody levels.
A recent study examined plasma cell homeostasis in mice by vaccinating animals with model antigens and then subjecting them to further vaccination with unrelated antigen or infection with a vaccine strain of Salmonella typhi [ 15 ]. This suggests that although polyclonal B cell activation had occurred, the final outcome was that competition for plasma cell survival was an overriding mechanism and that serological memory was lost following this antigenic insult.
Infection with Salmonella also resulted in a transient spike in the total number of splenic NP-specific plasma cells by 16 days post-infection but was followed by a trend showing lower NP-specific plasma cell numbers by 75 days post-infection. Again, pre-existing NP-specific serum antibody levels were lower in Salmonella -infected animals, indicating that bacterial infection reduced pre-existing vaccine-mediated antibody levels. In terms of clinical studies, direct competition between plasma cells for finite space does not appear to be a major issue for children undergoing routine vaccination as each new combination of vaccines must be tested to ensure adequate antibody responses to each of the individual vaccine components before the new combination of vaccines is accepted by the ACIP Advisory Committee on Immunization Practices and other regulatory bodies for inclusion in childhood immunization schedules.
For instance, the individual live attenuated measles, mumps, and rubella vaccines have been combined into the MMR vaccine. This vaccine has since been combined with the live attenuated varicella vaccine i. The seroconversion rates and levels of antibody to measles, mumps, rubella and varicella were not altered when the MMRV was co-administered with a booster dose of tetanus, diphtheria, acellular pertussis, hepatitis B virus, inactivated polio, and H.
We performed a small study to determine if infection or vaccination might alter pre-existing serum antibody responses in adult human subjects [ 27 ]. Four subjects received booster smallpox vaccination i. Although vaccinia-specific antibody titers were boosted by 8- to fold, there was no significant increase or decrease in pre-existing antibody levels specific for the 8 other vaccine or virus antigens. Similar to the subjects who received smallpox vaccination, no statistically significant increase or decrease in pre-existing serological memory to unrelated antigens was observed following successive rounds of vaccination or infection.
There may be several reasons why these results differ from that observed in mice [ 15 ]. In addition to the anticipated caveats associated with using different vaccine antigens with different doses and routes of vaccination, one possibility is that there may be differences between mouse and human immunology. On the other hand, a more interesting possibility for the difference between experimental results is that the timing of heterologous infection or vaccination could play a role in determining the fate of pre-existing plasma cells.
Perhaps there is a window of vulnerability in which newly generated plasma cells or plasmablasts are susceptible to inflammatory signals that result in decreased survival rates. This is an important question and further studies are needed to increase our basic understanding of this aspect of adaptive immunity, especially since it could play a role in determining the most appropriate vaccination schedules for conferring protective immunity in the clinical setting without potentially altering pre-existing serological memory.
Moreover, with substantial advances in flow cytometry instrumentation and reagents, a large number of T cell functions and phenotypic markers can be examined simultaneously. These studies, together with sophisticated microarray analysis of T cell gene expression profiles, have led to a wealth of information in understanding memory T cell responses.
However, the role of vaccine-induced antiviral T cell responses in protection against orthopoxviruses is unclear as an elegant study performed in non-human primates demonstrated that neutralizing antibodies were both necessary and sufficient for vaccine-mediated protection against lethal monkeypox infection, indicating that vaccine-induced T cells play only a minor role in protective immunity to this family of viruses [ 32 ]. Perhaps most perplexing is the failure of the STEP trial in which HIV-specific T cell responses were elicited by a 3-dose vaccination regimen, but failed to prevent HIV infection in field efficacy trials [ 42 ].
This latter case symbolizes the many challenges faced with development of T cell vaccines; although vaccine-induced T cells can be quantitatively measured, there is no accepted correlate of immunity that is based on a certain number of pre-existing T cells or type of vaccine-elicited T cell response. Bearing this in mind, it is difficult to know if an appropriate level of T cell memory has been reached or how protective the vaccine-induced T cells can be on their own — especially since there is growing consensus that for the most difficult infectious diseases e.
More work is needed in this area and identification and validation of T cell-specific correlates of immunity or co-correlates of immunity if both T cells and antibody are required for vaccine-mediated protection will be an important step forward in this field.
Adjuvants have been used extensively in clinical settings to enhance the efficacy of inactivated or recombinant vaccine antigens [ 43 — 45 ]. In general, adjuvants have been shown to increase the magnitude of vaccine-mediated immune responses, which may manifest as increased seroconversion rates, antigen dose sparing effects, or the ability to use fewer immunizations to achieve comparable levels of immunity [ 45 ]. However, there is also the expectation that advanced adjuvant systems, specifically those directed towards innate immune system signaling pathways, may be able to direct the type of immunity elicited following vaccination and better match pathogen-specific immunity requirements e.
A wide array of adjuvants have been developed, but due to high reactogenicity and associated safety concerns, only a limited number are currently used in licensed vaccines [ 44 ]. While the true mechanism by which these adjuvants potentiate immune responses remains controversial [ 47 ], their ability to enhance the levels of humoral immunity is well established, with pre-clinical reports dating back to [ 46 ].
Due to this history of safety and efficacy, aluminum salts continue to be used frequently in the development of new vaccine candidates. As a recent clinical example, an inactivated Ross River virus RRV vaccine candidate was tested at multiple antigen dose levels with or without aluminum hydroxide adjuvant [ 48 ].
Following three immunizations at the low dose vaccine level 1. Although alum is effective at boosting humoral immunity, this adjuvant may be limited with respect to induction of cellular immunity and this is one of the many reasons why it will be important to have additional adjuvant choices [ 45 ]. A range of new adjuvants directed towards innate immune system pathways in particular, Toll-like receptors, TLR have entered the clinical vaccine setting [ 44 , 45 ].
In a head-to-head comparison, the MPL-adjuvanted Cervarix vaccine elicited antibody responses that were approximately 2- to 9-fold higher than that observed with Gardasil [ 49 ]. Interestingly, despite the difference in absolute antibody titers, serum antibody decay patterns for both vaccines were remarkably similar, suggesting that the MPL-based adjuvant had increased the magnitude of antibody responses but had not fundamentally altered the subsequent kinetics of the humoral immune response.
In this study, the MPL adjuvant appeared to offer little to no benefit over the non-MPL-adjuvanted vaccine, suggesting that addition of a TLR-based adjuvant does not necessarily increase the breadth of the antiviral immune response.
There are several challenges to making direct comparisons between these different HPV vaccines since a the vaccine antigens, though similar, were generated through distinct manufacturing processes, b they contain different aluminum adjuvants aluminum hydroxide vs. Together, these clinical results indicate that advanced adjuvant formulations containing TLR agonists can indeed enhance humoral immunity, but extended follow-up is required to determine the duration of this effect since the difference in immunogenicity may be less apparent over time.
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. This does not appear to be the case since, with the possible exception of rubella, essentially all common childhood vaccines require booster vaccination regardless of whether they are non-replicating vaccines or live, attenuated vaccines Table 1.
However, unlike wild-type strains of measles and mumps, infection with the attenuated vaccine strains of these viruses is insufficient to provide long-term protective immunity after a single dose and a two-dose regimen is required in order to achieve sustained protection and broad herd immunity. Likewise, although recovery from natural polio infection will provide serotype-specific protection against reinfection, vaccination with the live, attenuated strains of virus used in the oral polio vaccine OPV or vaccination with formalin-inactivated polio virus IPV require multiple vaccinations in order to achieve sustained protective immunity.
Infection with Variola virus, the causative agent of smallpox, induces essentially lifelong immunity [ 52 ] and comparisons of antiviral antibody and T cell responses following infection with vaccinia i. In a small study examining the U. In contrast, modified vaccinia Ankura MVA represents a highly attenuated strain of vaccinia developed through serial in vitro passage.
This resulted in a virus that is largely incapable of replication in human cells and typically requires both high doses of virus and at least 3 vaccinations to elicit neutralizing antibody responses similar to one infection with vaccinia virus [ 55 ]. If only two MVA vaccinations are administered, then Another interesting comparison of durable immunity is between natural varicella infection i. Following recovery from primary varicella, strong antiviral immunity is developed and the virus enters latency. Based on these studies, the ACIP now recommends a two-dose schedule for varicella.
In this Table, examples of wild-type viruses that are known to elicit long-term protective immunity are compared to their vaccine counterparts, all of which require booster vaccination in order to achieve long-term protective immunity. Yellow fever is a mosquito-borne disease that elicits essentially lifelong immunity among survivors [ 58 ] and the live, attenuated yellow fever vaccine is often described as an example of how an effective vaccine can generate life-long immunity after a single dose.
However, this is only partially true since lifelong protection is only sustained in a subpopulation of vaccinated individuals. Prior to , yellow fever booster vaccination was recommended every 10 years but the World Health Organization recently modified their position, stating that a booster dose is no longer necessary [ 63 ]. This viewpoint is not shared by all experts in the field and several groups have questioned the basis for this position [ 64 , 65 ].
The bulk of evidence used to make the WHO decision on booster vaccination for yellow fever comes from a systematic review on this subject [ 66 ] and two of the larger independent studies described therein were performed in non-endemic countries i. 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 ].