Elephant in the room: natural killer cells don't forget HIV either.

Purpose Of Review: Like elephants (and T cells), accumulating evidence suggest natural killer (NK) cells never forget. The description of adaptive or memory NK cells, which can be induced by HIV/SIV infections and vaccines and associated with protective effects in persons with HIV (PWH), has dramatically increased the interest in leveraging NK cells to prevent HIV infection or suppress HIV reservoirs. However, harnessing their full antiviral potential has been hindered by an incomplete understanding of mechanisms underlying adaptive NK cell development and infected cell recognition.

HVTN 123: A Phase 1, Randomized Trial Comparing Safety and Immunogenicity of CH505TF gp120 Produced by Stably and Transiently Transfected Cell Lines.

Utilizing transiently transfected cell lines could significantly reduce manufacturing timelines for protein subunit vaccines. This trial compared safety and immunogenicity of human immunodeficiency virus (HIV) envelope CH505TF gp120 vaccines produced by upstream stable and transient transfection (each admixed with GLA-SE adjuvant, a TL4 agonist). Both vaccines were safe and well tolerated.

GeM-LR: Discovering predictive biomarkers for small datasets in vaccine studies.

Despite significant progress in vaccine research, the level of protection provided by vaccination can vary significantly across individuals. As a result, understanding immunologic variation across individuals in response to vaccination is important for developing next-generation efficacious vaccines. Accurate outcome prediction and identification of predictive biomarkers would represent a significant step towards this goal.

In utero human cytomegalovirus infection expands NK-like FcγRIII+CD8+ T cells that mediate Fc antibody functions.

Human cytomegalovirus (HCMV) profoundly impacts host T and NK cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III-expressing (FcγRIII-expressing) CD8+ T cells following HCMV exposure in utero. Most FcγRIII+CD8+ T cells express the canonical αβ T cell receptor (TCR), but a proportion express noncanonical γδ TCR.

A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.

To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple broadly neutralizing antibody (bNAb) combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs).

Safety and implementation of a phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.

Background: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.

Methods: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo.

Decreased variability in the site-specific results during participation in the External Quality Assurance Program Oversight Laboratory (EQAPOL) proficiency program for IFN-gamma enzyme-linked immunospot (IFN-γ ELISpot) assay.

The NIAID DAIDS-sponsored External Quality Assurance Program Oversight Laboratory (EQAPOL) manages an interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot) external proficiency program. The ELISpot program evaluates the accuracy and variability of results across laboratories. The variability in the program is quantified via the dispersion, which is the ratio of the variance over the mean of the background-corrected spot-forming cells (SFC) replicates obtained under stimulation with different peptide pools (CMV, CEF).

Loss of HIV candidate vaccine efficacy in male macaques by mucosal nanoparticle immunization rescued by V2-specific response.

Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIV acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17NKp44 innate lymphoid cells (ILCs). We investigated whether increased mucosal responses to V2 benefit vaccine efficacy by delivering oral nanoparticles (NPs) that release V2-scaffolded on Typhoid Toxin B (TTB) to the large intestine. Strikingly, mucosal immunization of male macaques abrogated vaccine efficacy with control TTB or empty NPs, but vaccine efficacy of up to 47.

Identification of RTS,S/AS01 vaccine-induced humoral biomarkers predictive of protection against controlled human malaria infection.

BACKGROUNDThe mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine-induced Plasmodium falciparum circumsporozoite protein-specific (PfCSP-specific) antibody measures associated with protection from controlled human malaria infection (CHMI). Here, we tested the protection-predicting capability of these measures in independent CHMI studies.

Non-HIV Vaccine-Induced Immune Responses as Potential Baseline Immunogenicity Predictors of ALVAC-HIV and AIDSVAX B/E-Induced Immune Responses.

Identifying correlations between immune responses elicited via HIV and non-HIV vaccines could aid the search for correlates of HIV protection and increase statistical power in HIV vaccine-efficacy trial designs. An exploratory objective of the HVTN 097 phase 1b trial was to assess whether immune responses [focusing on those supported as correlates of risk (CoR) of HIV acquisition] induced via the RV144 pox-prime HIV vaccine regimen correlated with those induced via tetanus toxoid (TT) and/or hepatitis B virus (HBV) vaccines. We measured TT-specific and HBV-specific IgG-binding antibody responses and TT-specific and HBV-specific CD4+ T-cell responses at multiple time points in HVTN 097 participants, and we assessed their correlations at peak time points with HIV vaccine (ALVAC-HIV and AIDSVAX B/E)-induced responses.

Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.

Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12.

Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies.

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A).

NK cells modulate in vivo control of SARS-CoV-2 replication and suppression of lung damage.

Natural killer (NK) cells play a critical role in virus control. However, it has remained largely unclear whether NK cell mobilization in SARS-CoV-2 infections is beneficial or pathologic. To address this deficit, we employed a validated experimental NK cell depletion non-human primate (NHP) model with SARS-CoV-2 Delta variant B.

Focusing HIV-1 Gag T cell responses to highly conserved regions by DNA vaccination in HVTN 119.

BACKGROUNDAn HIV-1 DNA vaccine composed of 7 highly conserved, structurally important elements (conserved elements, CE) of p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. DNA vaccination of CE prime/CE+p55Gag boost was compared with p55Gag.METHODSTwo groups (n = 25) received 4 DNA vaccinations (CE/CE+p55Gag or p55Gag) by intramuscular injection/electroporation, including IL-12 DNA adjuvant.

A comparative immunological assessment of multiple clinical-stage adjuvants for the R21 malaria vaccine in nonhuman primates.

Authorization of the Matrix-M (MM)-adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization for malaria prevention in children are a milestone in the fight against malaria. Yet, our understanding of the innate and adaptive immune responses elicited by this vaccine remains limited. Here, we compared three clinically relevant adjuvants [3M-052 + aluminum hydroxide (Alum) (3M), a TLR7/8 agonist formulated in Alum; GLA-LSQ, a TLR4 agonist formulated in liposomes with QS-21; and MM, the now-approved adjuvant for R21] for their capacity to induce durable immune responses to R21 in macaques.

Knockdowns of CD3zeta Chain in Primary NK Cells Illustrate Modulation of Antibody-Dependent Cellular Cytotoxicity Against Human Immunodeficiency Virus-1.

Multifaceted natural killer (NK) cell activities are indispensable for controlling human immunodeficiency virus (HIV)-1 transmission and pathogenesis. Among the diverse functions of NK cells, antibody-dependent cellular cytotoxicity (ADCC) has been shown to predict better HIV-1 protection. ADCC is initiated by the engagement of an Fc γ receptor CD16 with an Fc portion of the antibody, leading to phosphorylation of the CD3 ζ chain (CD3ζ) and Fc receptor γ chain (FcRγ) as well as downstream signaling activation.

Mosaic HIV-1 vaccine regimen in southern African women (Imbokodo/HVTN 705/HPX2008): a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: HIV type 1 (HIV-1) remains a global health concern, with the greatest burden in sub-Saharan Africa. Despite 40 years of research, no vaccine candidate has shown durable and protective efficacy against HIV-1 acquisition. Although pre-exposure prophylaxis in groups with high vulnerability can be very effective, barriers to its use, such as perceived low acquisition risk, fear of stigma, and concerns about side-effects, remain.

Safety and Immunogenicity of a DNA Vaccine With Subtype C gp120 Protein Adjuvanted With MF59 or AS01B: A Phase 1/2a HIV-1 Vaccine Trial.

Background: An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.

Innate protection against intrarectal SIV acquisition by a live SHIV vaccine.

Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies.

The Climate Change Burden on Immune Health: Are Persons Living with HIV More at Risk?

Climate change poses one of the most significant modern threats to overall human health,especially for vulnerable populations including persons living with HIV (PLWH). In this perspective, we specifically explore the concept of immune resilience in human health and how climate change phenomena - including extreme weather events, food insecurity, pollution, and emerging diseases - may exacerbate immune dysfunction and comorbidities faced by PLWH and hinder access to HIV treatment and prevention services. Multidisciplinary, collaborative efforts are urgently needed to quantify these impacts, develop mitigation strategies, and strengthen policies and funding to bolster immune resilience for PLWH in the face of accelerating climate change.

Natural killer-like B cells are a distinct but infrequent innate immune cell subset modulated by SIV infection of rhesus macaques.

Natural killer-like B (NKB) cells are unique innate immune cells expressing both natural killer (NK) and B cell receptors. As first responders to infection, they secrete IL-18 to induce a critical cascade of innate and adaptive immune cell infiltration and activation. However, limited research exists on the role of NKB cells in homeostasis and infection, largely due to incomplete and erroneous evaluations.

Safety and immunogenicity of a polyvalent DNA-protein HIV vaccine with matched Env immunogens delivered as a prime-boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial.

Background: An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens.

Methods: HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection.

FcαRI (CD89) is upregulated on subsets of mucosal and circulating NK cells and regulates IgA-class specific signaling and functions.

Immunoglobulin A (IgA) is the predominant mucosal antibody class with both anti- and pro-inflammatory roles. However, the specific role of the IgA receptor cluster of differentiation (CD)89, expressed by a subset of natural killer (NK) cells, is poorly explored. We found that CD89 protein expression on circulating NK cells is infrequent in humans and rhesus macaques, but transcriptomic analysis showed ubiquitous CD89 expression, suggesting an inducible phenotype.