Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy
Fredrik BarrenäsScott G. HansenG. Lynn LawConnor DriscollRichard GreenElise SmithJean ChangInah GolezTaryn UrionXinxia PengLeanne S. WhitmoreDaniel NewhouseColette M. HughesDavid W. MorrowKurt T. RandallAndrea N. SelsethJulia C. FordRoxanne M. GilbrideBryan E. RandallEmily AinslieKelli OswaldRebecca ShoemakerRandy FastWilliam J. BoscheMichael K. AxthelmYoshinori FukazawaGeorge N. PavlakisBarbara K. FelberSlim FouratiRafick‐Pierre SékalyJeffrey D. LifsonJan KomorowskiEwelina KosmiderDanica ShaoWenjun SongPaul T. EdlefsenLouis J. PickerMichael Gale
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Abstract:
Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68–1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8 + T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68–1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68–1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8 + T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8 + T cells to mediate protection against SIV challenge.Keywords:
Simian immunodeficiency virus
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Pathogens mutate as diseases spread, and variants that become epidemic or pandemic strains have higher transmission rates and a greater capacity to escape vaccine protection. Considering different vaccine efficacy and vaccination rates is of great significance for the prevention and control of infectious diseases. The spread of vaccination information and the level of trust in vaccinations determine whether people will choose to be vaccinated. To analyze these factors, we developed mean‐field equations for system dynamics to model the complex system of vaccine information dissemination and vaccination, calculated the basic reproduction rate number, and used the Icelandic COVID‐19 outbreak (Omicron variant) as a case study. We found that in the face of emerging variants, increasing vaccine efficacy is more effective than increasing vaccination rates. If vaccine efficacy increases from 40% to 90%, infections can be decreased by 98.5%. However, even a 100% vaccination rate cannot stop the spread of a mutated virus if vaccine efficacy falls below a certain level. High vaccination rates decrease the virus transmission rate. If the efficacy of the vaccine diminishes, the infection will spread rapidly, leading to a greater number of individuals becoming infected with the infectious disease. Due to the high vaccine efficacy against major illnesses and fatalities, improving vaccination rates can lower deaths. Iceland could decrease deaths by 44.8% by raising the vaccination rate from 75.9% to 95.0%. To combat emerging virus variants, it is therefore necessary to both create more effective vaccines and raise awareness of the benefits of vaccination to increase vaccination rates.
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An inactivated whole simian immunodeficiency virus (SIV) immunogen given to healthy, seropositive rhesus macaques 4 months after infection had no effect on the humoral immune response to SIV, the presence of antigenemia, cell-associated viremia, or disease course. Further immunotherapeutic trials in this highly susceptible animal model should be carried out sooner after exposure, before significant loss of CD4 cells has occurred. The SIV infected macaque model will continue to serve an essential role in development and testing of anti-AIDS drugs and immunogens.
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HIV/AIDS vaccines and also PrEP are considered as the most perspective approaches to control HIV/AIDS epidemic. Candidate conjugated polymer-subunit HIV vaccine VICHREPOL, developed in Moscow Institute of Immunology, successfully passed phase I clinical trials and now is at the start of phase II trials. Two other candidate vaccines (DNA-based and viral vector-based) are also passed phase I trials. Positive effect of vaccination depends of the coverage of population and this coverage depends of vaccine uptake. Estimation of possible uptake of HIV vaccine is very important to provide its further effective application. Pilot investigation of readiness for HIV vaccination in Russia (Moscow region) was performed [416 persons, 254 (61%)—men, 162 (39%)—women, age of 16–55]. Sixty percent of respondents were ready for HIV vaccination. Seventy nine percent of respondents with risk of HIV infection, agreed to be vaccinated vs 48% of those disclaimed the risk of HIV infection. Readiness for HIV vaccination is 20% lower in respondents with children vs childless. In case of 30% vaccine efficacy readiness for vaccination was 3.5 points of 10; in case of 50% efficacy—5.2 points of 10; 8.8 points of 10—in case of 90%–95% efficacy. Readiness for vaccination also depends from its duration, number of doses in course, possible adverse side effects, mode of vaccination. Twenty percent of respondents agreed only for free vaccination, 45%—for paid vaccination. Readiness for HIV vaccination is lower in general population (60% vs 78%) and in HIV infection risk groups (79% vs 95%–97%) in Russia vs some other countries (Suraratdecha et al., 2005). It is necessary to improve education programs aimed to inform on HIV vaccines development, its safety and application.
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Hyperattenuated simian immunodeficiency virus SIVmac239-derived constructs Delta5-CMV and Delta6-CCI are an effort to render SIV incapable of, in practical terms, both reversion and recombination while maintaining the immune features of SIV as a retrovirus. Primary inoculation of cynomolgus macaques with 10(8) 50% tissue culture infective doses (TCID(50)) of Delta5-CMV or Delta6-CCI induced low-level humoral and cellular responses detectable in the absence of measureable in vivo replication. The first of three DNA boosts resulted in elevated gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) responses to Gag, Pol, and Env in the Delta5-CMV vaccine group compared to the Delta6-CCI vaccine group (P = 0.001). Weekly intrarectal challenge with a low dose of SIVmac239 followed by a dose escalation was conducted until all animals became infected. The mean peak viral load of the Delta5-CMV-vaccinated animals (3.7 x 10(5) copies/ml) was approximately 1 log unit lower than that of the control animals. More dramatically, the viral load set point of these animals was decreased by 3 log units compared to that of the controls (<50 versus 1.64 x 10(4) copies/ml; P < 0.0001). Seventy-five percent (6/8) of vaccine recipients controlled virus below 1,000 copies/ml for at least 6 months, with a subset controlling virus and maintaining substantial CD4 T-cell counts for close to 2 years of follow-up. The correlates of protection from SIV disease progression may lie in the rapidity and protective value of immune responses that occur early in primary SIV infection. Prior immunization with hyperattenuated SIVmac239, even if sterilizing immunity is not achieved, may allow a more advantageous host response.
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Journal Article Evaluating Vaccination Effectiveness and Vaccine Efficacy by means of Case-Control Studies Get access George W. Comstock George W. Comstock Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins UniversityBaltimore, MD Dr. George W. Comstock, Training Center for Public Health Research, Box 2067, Hagerstown, MD 21742-2067 Search for other works by this author on: Oxford Academic PubMed Google Scholar Epidemiologic Reviews, Volume 16, Issue 1, 1994, Pages 77–89, https://doi.org/10.1093/oxfordjournals.epirev.a036147 Published: 01 March 1994 Article history Received: 23 July 1993 Revision received: 21 October 1993 Published: 01 March 1994
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For emerging diseases like pandemic influenza, several factors could impact the outcome of vaccination programs, including a delay in vaccine availability, imperfect vaccine-induced protection, and inadequate number of vaccines to sufficiently lower the susceptibility of the population by raising the level of herd immunity. We sought to investigate the effect of these factors in determining optimal vaccination strategies during an emerging influenza infection for which the population is entirely susceptible. We developed a population dynamical model of disease transmission and vaccination, and analyzed the control problem associated with an adaptive time-dependent vaccination strategy, in which the rate of vaccine distribution is optimally determined with time for minimizing the total number of infections (i.e., the epidemic final size). We simulated the model and compared the outcomes with a constant vaccination strategy in which the rate of vaccine distribution is time-independent. When vaccines are available at the onset of epidemic, our findings show that for a sufficiently high vaccine efficacy, the adaptive and constant vaccination strategies lead to comparable outcomes in terms of the epidemic final size. However, the adaptive vaccination requires a vaccine coverage higher than (or equivalent to) the constant vaccination regardless of the rate of vaccine distribution, suggesting that the latter is a more cost-effective strategy. When the vaccine efficacy is below a certain threshold, the adaptive vaccination could substantially outperform the constant vaccination, and the impact of adaptive strategy becomes more pronounced as the rate of vaccine distribution increases. We observed similar results when vaccines become available with a delay during the epidemic; however, the adaptive strategy may require a significantly higher vaccine coverage to outperform the constant vaccination strategy. The findings indicate that the vaccine efficacy is a key parameter that affects optimal control of vaccination dynamics during an epidemic, raising an important question on the trade-off between effectiveness and cost-effectiveness of vaccination policies in the context of limited vaccine quantities.
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Simian immunodeficiency virus (SIV) infection of macaques is a model for human immunodeficiency virus (HIV) infection. We have previously reported the construction and characterization of an SIV vector with a deletion in the nef gene (SIV(delta nef)) and expressing gamma interferon (SIV(HyIFN)) (L. Giavedoni and T. Yilma, J. Virol. 70:2247-2251, 1996). We now show that rhesus macaques vaccinated with SIV(HyIFN) have a lower viral load than a group similarly immunized with SIV(delta nef). Viral loads remained low in the SIV(HyIFN)-vaccinated group even though SIV expressing gamma interferon could not be isolated after 6 weeks postimmunization in these animals. All immunized and two naive control macaques became infected when challenged with virulent SIV(mac251), at 25 weeks postvaccination. In contrast to the two naive controls that died by 12 and 18 weeks postchallenge, all vaccinated animals remained healthy for more than 32 weeks. In addition, postchallenge cell-associated virus load was significantly lower in SIV(HyIFN)-immunized animals than in the group vaccinated with SIV(delta nef). These findings indicate that cytokine-expressing viruses can provide a novel approach for development of safe and efficacious live attenuated vaccines for AIDS.
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Mauricio A. Martins and David I. Watkins Department of Pathology, University of Miami, Miami, Florida 33136 Correspondence: dwatkins{at}med.miami.edu
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Analysis of rhesus macaques infected with a vpx deletion mutant virus of simian immunodeficiency virus mac239 (SIVΔvpx) demonstrates that Vpx is essential for efficient monocyte/macrophage infection in vivo but is not necessary for development of AIDS. To compare myeloid-lineage cell infection in monkeys infected with SIVΔvpx compared to SIVmac239, we analyzed lymphoid and gastrointestinal tissues from SIVΔvpx-infected rhesus (n = 5), SIVmac239-infected rhesus with SIV encephalitis (7 SIV239E), those without encephalitis (4 SIV239noE), and other SIV mutant viruses with low viral loads (4 SIVΔnef, 2 SIVΔ3). SIV+ macrophages and the percentage of total SIV+ cells that were macrophages in spleen and lymph nodes were significantly lower in rhesus infected with SIVΔvpx (2.2%) compared to those infected with SIV239E (22.7%), SIV239noE (8.2%), and SIV mutant viruses (10.1%). In colon, SIVΔvpx monkeys had fewer SIV+ cells, no SIV+ macrophages, and lower percentage of SIV+ cells that were macrophages than the other 3 groups. Only 2 SIVΔvpx monkeys exhibited detectable virus in the colon. We demonstrate that Vpx is essential for efficient macrophage infection in vivo and that simian AIDS and death can occur in the absence of detectable macrophage infection.
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