Vaccari et al. report that SIV vaccines formulated with two different adjuvants elicit distinct immune responses and effects on SIV acquisition in rhesus macaques. A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)–HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC–simian immunodeficiency virus (SIV) and gp120 alum (ALVAC–SIV + gp120) equivalent vaccine, but not an ALVAC–SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

The efficacy of ALVAC-based HIV and SIV vaccines in humans and macaques correlates with antibodies to envelope variable region 2 (V2). We show here that vaccine-induced antibodies to SIV variable region 1 (V1) inhibit anti-V2 antibody-mediated cytotoxicity and reverse their ability to block V2 peptide interaction with the α₄β₇ integrin. SIV vaccines engineered to delete V1 and favor an α helix, rather than a β sheet V2 conformation, induced V2-specific ADCC correlating with decreased risk of SIV acquisition. Removal of V1 from the HIV-1 clade A/E A244 envelope resulted in decreased binding to antibodies recognizing V2 in the β sheet conformation. Thus, deletion of V1 in HIV envelope immunogens may improve antibody responses to V2 virus vulnerability sites and increase the efficacy of HIV vaccine candidates.

The human papillomavirus pseudovirions (HPV-PsVs) approach is an effective gene-delivery system that can prime or boost an immune response in the vaginal tract of nonhuman primates and mice. Intravaginal vaccination with HPV-PsVs expressing SIV genes, combined with an i.m. gp120 protein injection, induced humoral and cellular SIV-specific responses in macaques. Priming systemic immune responses with i.m. immunization with ALVAC-SIV vaccines, followed by intravaginal HPV-PsV–SIV/gp120 boosting, expanded and/or recruited T cells in the female genital tract. Using a stringent repeated low-dose intravaginal challenge with the highly pathogenic SIVmac251, we show that although these regimens did not demonstrate significant protection from virus acquisition, they provided control of viremia in a number of animals. High-avidity Ab responses to the envelope gp120 V1/V2 region correlated with delayed SIVmac251 acquisition, whereas virus levels in mucosal tissues were inversely correlated with antienvelope CD4+ T cell responses. CD8+ T cell depletion in animals with controlled viremia caused an increase in tissue virus load in some animals, suggesting a role for CD8+ T cells in virus control. This study highlights the importance of CD8+ cells and antienvelope CD4+ T cells in curtailing virus replication and antienvelope V1/V2 Abs in preventing SIVmac251 acquisition.

The new pandemic virus SARS-CoV-2 emerged in China and spread around the world in <3 months, infecting millions of people, and causing countries to shut down public life and businesses. Nearly all nations were unprepared for this pandemic with healthcare systems stretched to their limits due to the lack of an effective vaccine and treatment. Infection with SARS-CoV-2 can lead to Coronavirus disease 2019 (COVID-19). COVID-19 is respiratory disease that can result in a cytokine storm with stark differences in morbidity and mortality between younger and older patient populations. Details regarding mechanisms of viral entry via the respiratory system and immune system correlates of protection or pathogenesis have not been fully elucidated. Here, we provide an overview of the innate immune responses in the lung to the coronaviruses MERS-CoV, SARS-CoV, and SARS-CoV-2. This review provides insight into key innate immune mechanisms that will aid in the development of therapeutics and preventive vaccines for SARS-CoV-2 infection.

The ALVAC-HIV clade B/AE and equivalent SIV-based/gp120 + Alum vaccines successfully decreased the risk of virus acquisition in humans and macaques. Here, we tested the efficacy of HIV clade B/C ALVAC/gp120 vaccine candidates + MF59 or different doses of Aluminum hydroxide (Alum) against SHIV-Cs of varying neutralization sensitivity in macaques. Low doses of Alum induced higher mucosal V2-specific IgA that increased the risk of Tier 2 SHIV-C acquisition. High Alum dosage, in contrast, elicited serum IgG to V2 that correlated with a decreased risk of Tier 1 SHIV-C acquisition. MF59 induced negligible mucosal antibodies to V2 and an inflammatory profile with blood C-reactive Protein (CRP) levels correlating with neutralizing antibody titers. MF59 decreased the risk of Tier 1 SHIV-C acquisition. The relationship between vaccine efficacy and the neutralization profile of the challenge virus appear to be linked to the different immunological spaces created by MF59 and Alum via CXCL10 and IL-1β, respectively. The ALVAC-based clade C /gp120 combination is currently being tested for efficacy and licensures in South Africa in the HVTN702 HIV vaccine trial using the MF59 adjuvant rather than Alum with the intent of inducing higher neutralizing antibodies and T cell responses. Here, we present studies in 71 macaques that evaluated the relative efficacy of identical ALVAC-HIV B/C HIV vaccines with Alum or MF59 following challenge exposure to SHIV-clade C viral stocks that differed in their neutralization profiles. Our results demonstrated that use of the proprietary Novartis Alum at lower doses affects the proportion of mucosal V2-specific IgG and IgA, and that IgAs and IgGs were respectively associated with an increased or decreased risk of virus acquisition. In contrast, animals immunized with the MF59 regimen had no V2 mucosal responses, and a high level of serum neutralizing antibodies (Tier 1) to easy to neutralize viruses that were associated with a decreased risk of Tier 1 SHIV-C acquisition. In vitro studies suggest the hypothesis that the low doses of proprietary Novartis Alum used in our studies may be the underlying reason for the decreased vaccine efficacy, via lower inflammasome activation and IL-1β production.