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Cross-Reactive CD8 T-Cell Responses Elicited by Adenovirus Type 5-Based HIV-1 Vaccines Contributed to Early Viral Evolution in Vaccine Recipients Who Became Infected.

ABSTRACT: Because of HIV's vast sequence diversity, the ability of the CD8 T-cell response to recognize several variants of a single epitope is an important consideration for vaccine design. Cross-recognition of viral epitopes by CD8 T cells is associated with viral control during HIV-1 infection, but little is known about CD8 cross-reactivity in the context of HIV-1 vaccination. Here, we evaluated vaccine-induced CD8 cross-reactivity in two preventative HIV-1 vaccine efficacy trials, the MRKAd5 and DNA/rAd5 studies. Cross-reactive CD8 responses elicited by vaccination were similar in magnitude and frequency to those induced during acute HIV-1 infection. Although responses directed against variant epitopes were less avid than responses to vaccine-matched epitopes, we did not detect any difference in response polyfunctionality (the proportion of cells producing multiple effector molecules). And while depth, or the frequency of cross-reactive responses, did not correlate with viral loads in recipients who became infected, cross-reactivity did appear to influence early viral evolution. In comparing viral sequences of placebo versus vaccine recipients, we found that viral sequences from vaccinees encoded CD8 epitopes with more substitutions and greater biochemical dissimilarity. In other words, breakthrough sequences of vaccinees would be less cross-recognized by vaccine-induced responses. Additionally, vaccine-induced CD8 T cells poorly cross-recognized variant epitopes encoding HLA-I-associated adaptations, further supporting our conclusion that these responses play a role in driving early HIV-1 viral evolution.IMPORTANCE HIV-1 has exceptionally high sequence diversity, much of which is found within CD8 epitopes. Therefore, the ability of CD8 T cells to recognize multiple versions of a single epitope could be important for an effective vaccine. Here, we show that two previously tested vaccines induced a similar level of CD8 cross-reactivity to that seen in acute HIV-1 infection. Although this cross-reactivity did not seem to affect viral control in vaccine recipients who became infected, we identified several ways in which CD8 cross-reactivity appeared to influence HIV-1 viral evolution. First, we saw that strains isolated from infected vaccine recipients would likely be poorly cross-recognized by the vaccine-induced response. Second, we saw that adapted CD8 epitopes were poorly cross-recognized in both vaccination and infection. Collectively, we believe these results show that CD8 cross-reactivity could be an important consideration in future HIV-1 vaccine design.

SUBMITTER: Boppana S

PROVIDER: S-EPMC6955250 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Cross-Reactive CD8 T-Cell Responses Elicited by Adenovirus Type 5-Based HIV-1 Vaccines Contributed to Early Viral Evolution in Vaccine Recipients Who Became Infected.

Boppana Sushma S Fiore-Gartland Andrew A Bansal Anju A Goepfert Paul P

Journal of virology 20200106 2

Because of HIV's vast sequence diversity, the ability of the CD8 T-cell response to recognize several variants of a single epitope is an important consideration for vaccine design. Cross-recognition of viral epitopes by CD8 T cells is associated with viral control during HIV-1 infection, but little is known about CD8 cross-reactivity in the context of HIV-1 vaccination. Here, we evaluated vaccine-induced CD8 cross-reactivity in two preventative HIV-1 vaccine efficacy trials, the MRKAd5 and DNA/r ...[more]

PMID: 31645444

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Project description:Influenza viruses have caused numerous pandemics throughout human history. The 1957 influenza pandemic was initiated by an H2N2 influenza virus. This H2N2 influenza virus was the result of a reassortment event between a circulating H2N2 avian virus and the seasonal H1N1 viruses in humans. Previously, our group has demonstrated the effectiveness of hemagglutinin (HA) antigens derived using computationally optimized broadly reactive antigen (COBRA) methodology against H1N1, H3N2, and H5N1 viruses. Using the COBRA methodology, H2 HA COBRA antigens were designed using sequences from H2N2 viruses isolated from humans in the 1950s and 1960s, as well as H2Nx viruses isolated from avian and mammalian species between the 1950s and 2016. In this study, the effectiveness of H2 COBRA HA antigens (Z1, Z3, Z5, and Z7) was evaluated in DBA/2J mice and compared to that of wild-type H2 HA antigens. The COBRA HA vaccines elicited neutralizing antibodies to the majority of viruses in our H2 HA panel and across all three clades as measured by hemagglutination inhibition (HAI) and neutralization assays. Comparatively, several wild-type HA vaccines elicited antibodies against a majority of the viruses in the H2 HA panel. DBA/2J mice vaccinated with COBRA vaccines showed increase survival for all three viral challenges compared to the wild-type H2 vaccines. In particular, the Z1 COBRA is a promising candidate for future work toward a pandemic H2 influenza vaccine.IMPORTANCE H2N2 influenza has caused at least one pandemic in the past. Given that individuals born after 1968 have not been exposed to H2N2 influenza viruses, a future pandemic caused by H2 influenza is likely. An effective H2 influenza vaccine would need to elicit broadly cross-reactive antibodies to multiple H2 influenza viruses. Choosing a wild-type virus to create a vaccine may elicit a narrow immune response and not protect against multiple H2 influenza viruses. COBRA H2 HA vaccines were developed and evaluated in mice along with wild-type H2 HA vaccines. Multiple COBRA H2 HA vaccines protected mice from all three viral challenges and produced broadly cross-reactive neutralizing antibodies to H2 influenza viruses.

Project description:ImportanceLive vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions.ObjectiveTo determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients.Design, setting, and participantsThis cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols.ExposuresExposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine.Main outcome and measureSafety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis.ResultsThe cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination.Conclusions and relevanceThe findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.

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Cross-Reactive CD8 T-Cell Responses Elicited by Adenovirus Type 5-Based HIV-1 Vaccines Contributed to Early Viral Evolution in Vaccine Recipients Who Became Infected.

Publications

Cross-Reactive CD8 T-Cell Responses Elicited by Adenovirus Type 5-Based HIV-1 Vaccines Contributed to Early Viral Evolution in Vaccine Recipients Who Became Infected.

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