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Optimal protection against malaria may require induction of high levels of protective antibody and CD8 + and CD4 + T cell responses. In humans, malaria DNA vaccines elicit CD8 + cytotoxic T cells (CTL) and IFNγ responses as measured by short-term (ex vivo) ELISPOT assays, and recombinant proteins elicit antibodies and excellent T cell responses, but no CD8 + CTL or CD8 + IFNγ-producing cells as measured by ex vivo ELISPOT. Priming with DNA and boosting with recombinant pox virus elicits much better T cell responses than DNA alone, but not antibody responses. In an attempt to elicit antibodies and enhanced T cell responses, we administered RTS,S/AS02A, a partially protective Plasmodium falciparum recombinant circumsporozoite protein (CSP) vaccine in adjuvant, to volunteers previously immunized with a P. falciparum CSP DNA vaccine (VCL-2510) and to naı̈ve volunteers. This vaccine regimen was well tolerated and safe. The volunteers who received RTS,S/AS02A alone had, as expected, antibody and CD4 + T cell responses, but no CD8 + T cell responses. Volunteers who received PfCSP DNA followed by RTS,S/AS02A had antibody and CD8 + and CD4 + T cell responses (Wang et al., submitted). Sequential immunization with DNA and recombinant protein, also called heterologous prime-boost, led to enhanced immune responses as compared to DNA or recombinant protein alone, suggesting that it might provide enhanced protective immunity.

The prime–boost response induced by different combinations of four H5N1 vaccines (NIBRG-14 (clade 1), Indo05/2005(H5N1)/PR8-IBCDC-RG2 (clade 2.1), A/Bar-Headed Goose/Qinhai Lake/1A/05 SJ163222 (clade 2.2), and Anhui01/2005(H5N1)-PR8-IBCDC-RG5 (clade 2.3.4)) was evaluated in mice. Clade 1-primed BALB/c mice showed a booster response to all of the other three H5N1 vaccines. Clade 2.2 vaccine was also a good priming vaccine. However, mice primed with clade 2.1 or clade 2.3.4 vaccine did not respond to booster injection with clade 1 vaccine, suggesting that priming might actually inhibit the booster response with some combinations of vaccines belonging to different clades. Analysis of the mechanism involved showed that lymphocytes from primed mice secreted comparable amounts of cytokines with any combination of priming and booster vaccines. Therefore, impairment of B cell immunity specific to certain booster strains may have been involved.

Airway mucosa represents the main entry point for several human pathogens, and as such vaccines against respiratory diseases should ideally elicit protective immune responses in the airways. We have previously reported two immunomodulatory adjuvants based on non-toxic derivatives of Cholera toxin (CT), namely mmCT and CTB-CpG with strong ability to mount mucosal immune responses. Herein, we aimed to pinpoint the potential of prime-boost immunization approaches using the fusion-protein based subunit vaccine candidate H56 as a model antigen, combined with adjuvants CAF01, mmCT, and CTB-CpG in mice. This included a parenteral H56+CAF01 priming followed by an intranasal boost with H56+CAF01, H56+mmCT, or H56+CTB-CpG, compared with repeated homologous intranasal administrations of H56 with each adjuvant. We observed that a parenteral prime with H56+CAF01 followed by an intranasal H56+CTB-CpG booster immunization triggered a Th1-skewed immune response. Conversely, combining the parenteral H56+CAF01 prime with an intranasal H56+mmCT boost resulted in a mixed Th1/Th17-skewed immune response. Notably, the latter combination also engendered anamnestic, long-lived T-cell responses in the lungs which homologous intranasal H56+mmCT immunizations failed to induce. These results suggest that an immunization regimen consists of parenteral priming with H56+CAF01 followed by an airway boosting with H56 protein and mucosal adjuvants holds promise in mounting combined systemic and mucosal immune responses to , and as such warrants further exploration. Given the rising interest in mucosal vaccines for respiratory pathogens, these findings offer an important immunological framework for future translational studies.

The introduction of pneumococcal conjugate vaccines (PCVs) 7 and 13 into national childhood immunization programs in the US in 2000 and 2010, respectively, proved to be remarkably successful in reducing infant mortality due to invasive pneumococcal disease (IPD), resulting in widespread uptake of these vaccines. Secondary herd protection of non-vaccinated adults against IPD has proven to be an additional public health benefit of childhood immunization with PCVs, particularly in the case of the vulnerable elderly who are at increased risk due to immunosenescence and underlying comorbidity. Despite these advances in pneumococcal immunization, the global burden of pneumococcal disease, albeit of unequal geographic distribution, remains high. Reasons for this include restricted access of children living in many developing countries to PCVs, the emergence of infection due to non-vaccine serotypes of the pneumococcus, and non-encapsulated strains of the pathogen. Emerging concerns affecting the elderly include the realization that herd protection conferred by the current generation of PCVs (PCV7, PCV10, and PCV13) has reached a ceiling in many countries at a time of global population aging, compounded by uncertainty surrounding those immunization strategies that induce optimum immunogenicity and protection against IPD in the elderly. All of the aforementioned issues, together with a consideration of pipeline and pending strategies to improve access to, and serotype coverage of, PCVs, are the focus areas of this review.

Following the conclusion of the COVID-19 pandemic, the persistent genetic variability in the virus and its ongoing circulation within the global population necessitate the enhancement of existing preventive vaccines and the development of novel ones. A while back, we engineered an orally administered probiotic-based vaccine, L3-SARS, by integrating a gene fragment that encodes the spike protein S of the SARS-CoV-2 virus into the genome of the probiotic strain E. faecium L3, inducing the expression of viral antigen on the surface of bacteria. Previous studies demonstrated the efficacy of this vaccine candidate in providing protection against the virus in Syrian hamsters. In this present study, utilizing laboratory mice, we assess the immune response subsequent to immunization via the gastrointestinal mucosa and discuss its potential as an initial phase in a two-stage vaccination strategy. Our findings indicate that the oral administration of L3-SARS elicits an adaptive immune response in mice. Pre-immunization with L3-SARS enhances and prolongs the humoral immune response following a single subcutaneous immunization with a recombinant S-protein analogous to the S-insert of the coronavirus in Enterococcus faecium L3.

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated . Mice were immunized with a combination of live pPst Δ , live pPst Δ /Δ , or recombinant F1-V (rF1-V) combined with adjuvants. The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.

Background The porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause widespread infections in the pig industry worldwide. Currently, multiple PRRSV vaccine candidates are in preclinical or clinical trials, and each has different advantages and limitations. Glycoprotein 4 (GP4) is rich in epitopes, which can induce the body to produce neutralizing antibodies, plays a vital role in causing the host immune response, and is a key target for PRRSV vaccine development. In this study, we developed a novel candidate vaccine immunization strategy combining a subunit vaccine with an adenovirus vector vaccine through prokaryotic and eukaryotic systems expressing GP4. Results In this study, predictive analysis of PRRSV GP4 antigen structures in two expressed modes, and the results showed good antigenicity. The PRRSV GP4 subunit vaccine, as well as the adenovirus vector-based vaccine, were successfully constructed. In the immunization experiment of mouse models, a heterologous primary-boost immunization strategy was implemented: primary immunization with the GP4 subunit vaccine, and boost immunization was followed by an adenovirus vector vaccine. The safety assessment revealed that all candidate vaccine groups demonstrated good safety profiles. With an indirect enzyme-linked immunosorbent assay (ELISA) and neutralizing antibodies, mice in the combined immunization group developed higher levels of PRRSV-specific antibodies with significantly higher neutralizing antibody titers than mice alone. IgG subtype analysis indicated that the proteome favors the Th2-type immune response, while the adenoviral group favors the Th1-type immune response. The secretion levels of cytokines IL-4, IFN-γ, and TNF-α were significantly higher in the serum of the combined immunization group than in the immune group alone. Moreover, the cellular immune response test results showed that the combined immune group significantly enhanced the splenic lymphocyte proliferation capacity, IFN-γ secretion level, and cytokine transcript level. These findings suggest that the heterologous primary-boost immunization strategy of the PRRSV GP4 subunit vaccine developed here, in combination with the adenovirus vaccine, successfully induced strong humoral and cellular immune responses in mice. Conclusions In this study, the PRRSV GP4 subunit and adenovirus vector vaccine were successfully constructed and induced high levels of PRRSV-specific neutralizing antibody and cellular immune responses in mouse models by a heterologous primary-boost immunization strategy. These results support the clinical development of the PRRSV vaccine and bring new hope for PRRSV prevention and control strategies in the swine industry.

Pre-existing anti-vector immunity can severely compromise the ability of Salmonella enterica serovar Typhimurium live vaccines to induce protective CD8 T-cell frequencies after type III secretion system-mediated heterologous protein translocation in orally immunized mice. In the present study, we demonstrate that heterologous prime–boost immunizations using attenuated serovar Typhimurium and serovar Dublin strains for foreign antigen delivery can be employed to bypass anti- Salmonella immunity resulting in enhanced antigen-specific CD8 T-cell induction. This desirable effect can be explained by the fact that, in contrast to homologous prime–boost immunizations, vaccination with different Salmonella serovars is characterized by long-lasting colonization of mice by both live carrier vaccines.

Dengue is one of the most important diseases transmitted by mosquitoes. Dengvaxia®, a vaccine registered in several countries, cannot be administered to non-immune individuals and children younger than 9 years old, due to safety reasons. There are two vaccine candidates in phase 3 efficacy trials, but their registration date is completely unknown at this moment. So, the development of new vaccines or vaccine strategies continues to be a priority for the WHO. This work reviews some complementary prime-boost immunization studies against important human pathogens. Additionally, it reviews the results obtained using this regimen of immunization against dengue virus as a potential alternative approach for finding a safe and efficient vaccine. Finally, the main elements associated with this strategy are also discussed. The generation of new strategies of vaccination against dengue virus, must be directed to reduce the risk of increasing viral load through sub-neutralizing antibodies and it must be also directed to induce a polyfunctional T cell response. Complementary prime-boost immunization strategies could emerge as an interesting approach to induce solid immunity or at least to reduce viral load after natural infection, avoiding severe dengue. Subunit vaccine could be safe and attractive antigens for this strategy, especially proteins including B, and T-cells epitopes for inducing humoral and cellular immune responses, which can play an important role controlling the disease.