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Abstract
South African trial halted early because of "futility."
... Even though the RV144 trial showed modest efficacy in regard of protection, an on-going vaccine trial based on the RV144 vaccination study -a trial termed HVTN 702 and conducted in South Africa since 2016 -had to halt further scheduled vaccinations due to a lack of evidence of efficacy. Here, a vaccination approach similar to the RV144 trial was used -with an adaptation of the vaccine to the circulating South African clade C HIV strain [122]. ...
... In the context of HIV vaccination, this has been shown for the RV144 trial in Thailand and the subsequent follow-up study in South Africa termed HVTN 702, respectively. While alum, an aluminium hydroxide-based adjuvant, was used together with bivalent gp120 subunits in the RV144 booster immunization, the adjuvant choice for HVTN 702 moved to the more immunogenic squalene-based MF59 [102,122,123]. Interestingly, in contrast to the RV144 trial showing moderate long-lasting protection against HIV acquisition, the scheduled vaccinations of the HVTN 702 trial had to be prematurely halted due to a lack of efficacy [122]. ...
... While alum, an aluminium hydroxide-based adjuvant, was used together with bivalent gp120 subunits in the RV144 booster immunization, the adjuvant choice for HVTN 702 moved to the more immunogenic squalene-based MF59 [102,122,123]. Interestingly, in contrast to the RV144 trial showing moderate long-lasting protection against HIV acquisition, the scheduled vaccinations of the HVTN 702 trial had to be prematurely halted due to a lack of efficacy [122]. Even though also the utilized vectors and proteins were adjusted to the circulating HIV strain in South Africa, this differential outcome might be partly attributed to the utilized adjuvant. ...
After almost 40 years of HIV research, an effective prophylactic vaccine capable of coping with the global HIV pandemic still remains elusive. A substantial problem in this context is the sole antibody-targetable surface protein Env, which – in contrast to other viral surface proteins – induces a predominant TH2-associated antibody response. However, the modulation of T helper cell polarization towards a more pronounced TH1 response with subsequent production of an appropriate anti-Env IgG subclass is still a challenging task. One possibility to influence Env-specific adaptive immune responses represents intrastructural help. Nevertheless, for maximal efficacy, this strategy requires a priming immunization with HIVindependent structural proteins - a resource- and time-intensive step with its applicability also heavily depending on the respective vaccination coverage. The utilization of vaccine adjuvants within the vaccine composition might be an alternative approach to influence the vaccine-induced T helper cell polarization. However, up to date no distinctly TH1-modulating HIV-1 adjuvant is available. Immune checkpoints as membrane-bound receptors and ligands expressed on T lymphocytes play an important role in the regulation of T cell responses and physiologically keep inflammatory processes at bay. Blocking immune checkpoints of the inhibitory PD-1/PD-L1 axis by monoclonal antibodies results in a pronounced activation of the immune system which can be utilized for the immunomodulatory treatment of various cancers. In this study, BALB/c mice received systemic administration of checkpoint inhibitors (CPIs) targeting PD-1 and its ligands via intraperitoneal injection after HIV-1 VLP and DNA immunization. However, here no modulatory effects on antiviral cellular and humoral immune responses were observable. Furthermore, a competitive immune response directed against the treatment antibodies was elicited involving a spontaneous production of TH2-cytokines and subsequent CPI-directed antibody response. To circumvent those side effects after systemic administration, a local approach to block immune checkpoints in vivo was conducted by intramuscular electroporation of antigenic DNA together with plasmids encoding for soluble ectodomains of PD-1 (sPD-1) and PD-L1 (sPD-L1). Here, the co-electroporation of sPD-L1 resulted in an elevated Env-specific TH1-responses and a rapid production of Env-specific IgG2a antibodies. Moreover, differential effects of the soluble ectodomains on suppressive regulatory T cell populations were observable. By analysing splenic T cells of immunized mice and performing antigen-specific in vitro co-cultures, a potential involvement of T-follicular helper cells during CPI-modulated adaptive immune responses is indicated. Since HIV-1 Env resembles an exceptional antigen within the group of viral glycoproteins, genetic immunization experiments with simultaneous expression of checkpoint ectodomains were performed for HA of Influenza A, a glycoprotein inducing a TH1-biased immune response in mice. Here, in contrast to Env, the genetic adjuvantation with sPD-1 resulted in a vaccine-induced modulation involving a more pronounced T cell response, decreased suppressive T cell frequencies and a balanced antibody subtype pattern. The presented data indicate a modulatory capacity of blocking the inhibitory PD-1/PD-L1 axis in regard of vaccine-induced cellular and humoral immune responses – a phenomenon which seems to be dependent on the respective antigen. Whether the induced balanced antibody subtype pattern is beneficial in regard of secondary effector functions and therefore vaccine-induced protection, needs to be further elucidated. Clinically, this might be important especially for the risk group of CPI-treated cancer patients, which might differentially react to vaccines.
... Panels i and j adapted with permission from ref. 153 , Wiley. Panels k and l adapted from ref. 148 , distributed under a CC BY 4.0 license (http://creativecommons.org/licenses/by/4.0/). of RV144 (HVTN 702) was halted prematurely due to the lack of efficacy 29 . In this trial, HIV-1 subtype C antigens were included in the vaccine in order to increase coverage against the virus strains circulating in South Africa, which has infection rates significantly higher than in Thailand. ...
... In this trial, HIV-1 subtype C antigens were included in the vaccine in order to increase coverage against the virus strains circulating in South Africa, which has infection rates significantly higher than in Thailand. Whether differences in vaccine regimens, infection rates, or trial populations contributed to the differences observed between the two trials is still unclear 29 . Vaccination studies in non-human primates have also supported a protective role for non-neutralizing Fc-mediated effector functions 30,31 . ...
Despite the overwhelming success of vaccines in preventing infectious diseases, there remain numerous globally devastating diseases without fully protective vaccines, particularly human immunodeficiency virus (HIV), malaria and tuberculosis. Nanotechnology approaches are being developed both to design new vaccines against these diseases as well as to facilitate their global implementation. The reasons why a given pathogen may present difficulties for vaccine design are unique and tied to the co-evolutionary history of the pathogen and humans, but there are common challenges that nanotechnology is beginning to help address. In each case, a successful vaccine will need to raise immune responses that differ from the immune responses raised by normal infection. Nanomaterials, with their defined compositions, commonly modular construction, and length scales allowing the engagement of key immune pathways, collectively facilitate the iterative design process necessary to identify such protective immune responses and achieve them reliably. Nanomaterials also provide strategies for engineering the trafficking and delivery of vaccine components to key immune cells and lymphoid tissues, and they can be highly multivalent, improving their engagement with the immune system. This Review will discuss these aspects along with recent nanomaterial advances towards vaccines against infectious disease, with a particular emphasis on HIV/AIDS, malaria and tuberculosis.
... After 40 years since the detection of the first HIV case, the HIV pandemic is far from over with around 1.5 million people acquiring HIV and 680,000 AIDS-related deaths in 2020 (UNAIDS 2021). Despite global efforts, the development of an effective vaccine against HIV remains elusive (Cohen 2020;Ng'uni et al. 2020) mainly due to the rapid HIV evolution (Cuevas et al. 2015) and tissue reservoirs of HIV-infected T-cells (Fromentin and Chomont 2020;Lorenzo-Redondo et al. 2016). Hence, the currently available antiretroviral therapy against this virus is based on a diverse repertoire of drugs that include chemokine receptor antagonisms, inhibitors of the viral fusion with the cellular membrane and inhibitors of the viral replication machinery such as the reverse transcriptase (RT), integrase (IN) and protease (PR), among others (see for a review Arts & Hazuda, 2012). ...
The evolution of structural proteins is generally constrained by the folding stability. However, little is known about the particular capacity of viral proteins to accommodate mutations that can potentially affect the protein stability and, in general, the evolution of the protein stability over time. As an illustrative model case, here we investigated the evolution of the stability of the HIV-1 protease (PR), which is a common HIV-1 drug target, under diverse evolutionary scenarios that include (i) intra-host virus evolution in a cohort of 75 patients sampled over time, (ii) intra-host virus evolution sampled before and after specific PR-based treatments and, (iii) inter-host evolution considering extant and ancestral (reconstructed) PR sequences from diverse HIV-1 subtypes. We also investigated the specific influence of currently known HIV-1 PR resistance mutations on the PR folding stability. We found that the HIV-1 PR stability fluctuated over time within a constant and wide range in any studied evolutionary scenario, accommodating multiple mutations that partially affected stability while maintaining activity. We did not identify relationships between change of PR stability and diverse clinical parameters such as viral load, CD4+ T cell counts and a surrogate of time from infection. Counterintuitively, we predicted that near half of the studied HIV-1 PR resistance mutations do not significantly decrease stability, which together with compensatory mutations, would allow the protein to adapt without requiring dramatic stability changes. We conclude that the HIV-1 PR presents a wide structural plasticity to acquire molecular adaptations without affecting the overall evolution of stability.
... While the vaccination regimen was principally not changed, it was adjusted to the circulating clade C strain and the adjuvant used for the gp120 subunit boost was substituted by the more immunogenic squalene-based MF59 106 . Unfortunately, due to a lack of efficacy, all scheduled vaccinations were stopped early 107,108 . Whether this outcome was related to adjuvant-induced modulations of the immune system, or the involvement of other possible factors needs to be elucidated. ...
The induction of a potent and long-lasting, broadly-neutralizing antibody response is generally considered one of the most promising approaches for human immunodeficiency virus (HIV) vaccination. Interestingly, several clinical and pre-clinical studies indicate a potential association of IgG Fc effector functions and their protective capacity. However, Env as the only HIV surface glycoprotein and main target of the humoral immune response, was shown to induce a largely TH2-associated IgG1 dominated antibody response, known for its low Fc receptor functionality. Recently, we demonstrated that Gag-specific T helper cells induced by DNA priming can enhance and modulate the HIV Env-specific B cell response upon virus-like particle (VLP) boost by intrastructural help (ISH), resulting in a more desirable TH1 associated IgG2a response. To minimize the induction of potentially harmful HIV-specific TH cells, this study investigates the possibility to harness heterologous TH cell responses induced by licensed and experimental vaccines. Based on the correlation of TH subtypes and IgG isotype, a detailed analysis of the respective TH cell response by differently adjuvanted licensed Hepatitis B vaccines was performed. To provide ISH, identified MHC-II restricted Hepatitis B surface antigen (HBsAg) derived peptides were genetically incorporated into the HIV Gag protein and used for VLP generation. ISH effects on Env-specific antibody levels were analyzed in mice primed with Engerix, Fendrix, Heplisav-B, or HBsAg DNA and boosted with VLPs. Although the respective vaccination regimens failed to modulate the Env-specific IgG response in a statistically significant manner, mice that received a TH1-promoting Hepatitis B priming showed trends towards IgG2a or IgG2c dominated immune responses. Accordingly, the experimental tuberculosis subunit vaccine H1 (Hybrid 1 fusion protein) in combination with the liposomal adjuvant CAF01, previously shown to induce a strong and long-lasting TH1 response, was used for equivalent mouse immunization experiments. Env-specific antibody levels and B cell differentiation were analyzed in mice primed against H1 and boosted with VLPs containing H1 T helper epitopes. Here, in contrast to non-primed mice, a significant increase of Env-specific IgG levels for up to 26 weeks after the last immunization was observed. This increase was largely caused by elevated IgG2b and IgG2c levels in mice that received H1 priming. Additionally, ISH enhanced the frequency of Env-specific long lived plasma cells in the bone marrow. The presented data highlight the modulatory potential of heterologous CD4+ T cells, harnessed by ISH for the modulation and enhancement of the Env humoral response, providing valuable insight to further increase efficacy of potential HIV vaccines.
... A variety of HIV-1 vaccine approaches have been evaluated in preclinical models and clinical studies, but the results have been, overall, unsatisfactory [6][7][8] . Only a single human vaccine trial, the RV144 study in Thailand, has hitherto yielded a low degree of protec-tion (~30%), although it failed to elicit bNAbs and its partial success was not reproduced in recent attempts at corroboration in clinical trials conducted in Africa [9][10][11] . Preclinical studies with soluble forms of the HIV-1 Env trimer stabilized in a configuration similar to that presented on native viral particles, such as SOSIP trimers and variations thereof [12][13][14][15][16][17] , have documented robust induction of autologous neutralizing antibodies, primarily targeting strain-specific holes in the Env glycan shield, accompanied by large amounts of off-target, non-neutralizing antibodies primarily directed at the trimer base, further emphasizing the challenges in eliciting bNAbs by vaccination [18][19][20][21][22][23] . ...
The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4+ T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian–human immunodeficiency virus (SHIV AD8). Thus, the multiclade env–gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine. An mRNA vaccine platform to prevent HIV-1 infection generated broadly neutralizing antibodies in non-human primates and protected some animals from infection, raising hope that optimization of this approach might lead to an effective HIV vaccine.
... Understanding early immune engagement is likely to provide new strategies for rational and successful vaccine design, particularly for key pathogens where large-scale vaccine efforts have thus far failed, e.g. human immunodeficiency virus-1 (HIV-1) 3 and hepatitis C virus (HCV) 4,5 . ...
Effective vaccines for human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) remain a significant challenge for these infectious diseases. Given that the innate immune response is key to controlling the scale and nature of developing adaptive immune responses, targeting natural killer (NK) cells that can promote a T-helper type 1 (Th1)-type immune response through the production of interferon-γ (IFNγ) remains an untapped strategic target for improved vaccination approaches. Here, we investigate metabolic and functional responses of NK cells to simian adenovirus prime and MVA boost vaccination in a cohort of healthy volunteers receiving a dual HCV-HIV-1 vaccine. Early and late timepoints demonstrated metabolic changes that contributed to the sustained proliferation of all NK cells. However, a strong impact of human cytomegalovirus (HCMV) on some metabolic and functional responses in NK cells was observed in HCMV seropositive participants. These changes were not restricted to molecularly defined adaptive NK cells; indeed, canonical NK cells that produced most IFNγ in response to vaccination were equally impacted in individuals with latent HCMV. In summary, NK cells undergo metabolic changes in response to vaccination, and understanding these in the context of HCMV is an important step towards rational vaccine design against a range of human viral pathogens.
... Rectal, vaginal and lymph node tissues were biopsied on the day of first vaccination and 2 weeks after each vaccination. Plasma and PBMC were isolated from EDTA anti-coagulated whole blood using established protocols (68). Isolation of mononuclear cells (MNC) from colon-rectal mucosa was carried out according to previously published procedures (69). ...
We modified a Sabin Oral Poliovirus Vaccine (OPV) vector to permit secretion of the antigens of interest with the goal of improving anti-HIV Env humoral responses in a SHIV mucosal immunization composed of DNA and recombinant OPVs. We evaluated stimulation of systemic and mucosal cell-mediated and humoral immunity in Rhesus macaques by two regimens, both involving a prime with a SHIVBG505 DNA construct producing non-infectious particles formulated in lipid nanoparticles, administered in the oral cavity, and two different viral vector boostings, administered in the oral cavity and intestinally. Group 1 was boosted with rMVA-SHIVBG505, expressing SIV Gag/Pol and HIVBG505 Env. Group 2 was boosted with a SHIVBG505-OPV vaccine including a non-secreting SIVmac239CA-p6-OPV, expressing Gag CA, NC and p6 proteins, and a HIVBG505C1-V2-OPV, secreting the C1-V2 fragment of HIV EnvBG505, recognized by the broadly neutralizing antibody PG16. A time course analysis of anti-SHIV Gag and Env CD4+ and CD8+ T-cell responses in PBMC and in lymph node, rectal, and vaginal MNC was carried out. Both regimens stimulated significant cell-mediated responses in all compartments, with SHIVBG505-OPV immunization stimulating more significant levels of responses than rMVA- SHIVBG505. Boolean analysis of these responses revealed predominantly monofunctional responses with multifunctional responses also present in all tissues. Stimulation of antibody responses was disappointing in both groups with negative anti-SHIV IgG in plasma, and IgA in salivary, rectal and vaginal secretions being restricted to a few animals. After repeated rectal challenge with SHIVBG505, two Group 1 animals remained uninfected at challenge termination. No significant differences were observed in post-infection viral loads between groups. After the acute phase decline, CD4+ T cell percentages returned to normal levels in vaccinated as well as control animals. However, when compared to controls, vaccinate groups had more significant preservation of PBMC and rectal MNC Th17/Treg ratios, considered the strongest surrogate marker of progression to AIDS. We conclude that the vaccine platforms used in this study are insufficient to stimulate significant humoral immunity at the tested doses and schedule but sufficient to stimulate significant mucosal and systemic cell-mediated immunity, impacting the preservation of key Th17 CD4+ T cells in blood and rectal mucosa.
... In fact, albeit the Antiretroviral Therapy (ART) has achieved great success in HIV treatment, there is a sub-optimal treatment coverage of infected people (only the 64% according to UNAIDS 2019). The recent fail of pioneering projects of eradication of the infection 2 or immunisation, 3 together with raises the number of treatment failures 4 due to selection and transmission of drugresistant variants [5][6][7] , enlight the constant need of finding new drugs with innovative mechanisms of action. ...
Bioassay-guided fractionation of the ethyl acetate extract from Teucrium flavum subsp. glaucum, endowed with inhibitory activity towards the HIV-1 reverse transcriptase–associated RNase H function, led to the isolation of salvigenin (1), cirsimaritin (2) and cirsiliol (3) along with the neo-clerodanes teuflavin (4) and teuflavoside (5). Acid hydrolysis of the inactive teuflavoside provided three undescribed neo-clerodanes, flavuglaucins A-C (7-9) and one known neo-clerodane (10). Among all neo-clerodanes, flavuglaucin B showed the highest inhibitory activity towards RNase H function with a IC50 value of 9.1 μM. Molecular modelling and site-directed mutagenesis analysis suggested that flavuglaucin B binds into an allosteric pocket close to RNase H catalytic site. This is the first report of clerodane diterpenoids endowed with anti-reverse transcriptase activity. Neo-clerodanes represent a valid scaffold for the development of a new class of HIV-1 RNase H inhibitors.
... The RV144 trial employing a recombinant canarypox (ALVAC-HIV) prime and envelope (Env) gp120 protein (AIDSVAX B/E) boost vaccine approach showed evidence of a modest protective effect, and gave hope that a protective HIV vaccine is ultimately achievable (8,9). However, the more recent failure of HVTN 702 in South Africa, which utilized the same poxvirus prime/gp120 boost strategy, underlines the need for novel approaches (10). The immune correlates required for an HIV vaccine to provide protection in human populations remain incompletely defined. ...
The search for a preventive vaccine against HIV infection remains an ongoing challenge, indicating the need for novel approaches. Parainfluenza virus 5 (PIV5) is a paramyxovirus replicating in the upper airways that is not associated with any animal or human pathology. In animal models, PIV5-vectored vaccines have shown protection against influenza, RSV, and other human pathogens. Here, we generated PIV5 vaccines expressing HIV envelope (Env) and SIV Gag and administered them intranasally to macaques, followed by boosting with virus-like particles (VLPs) containing trimeric HIV Env. Moreover, we compared the immune responses generated by PIV5-SHIV prime/VLPs boost regimen in naïve vs a control group in which pre-existing immunity to the PIV5 vector was established. We demonstrate for the first time that intranasal administration of PIV5-based HIV vaccines is safe, well-tolerated and immunogenic, and that boosting with adjuvanted trimeric Env VLPs enhances humoral and cellular immune responses. The PIV5 prime/VLPs boost regimen induced robust and durable systemic and mucosal Env-specific antibody titers with functional activities including ADCC and neutralization. This regimen also induced highly polyfunctional antigen-specific T cell responses. Importantly, we show that diminished responses due to PIV5 pre-existing immunity can be overcome in part with VLP protein boosts. Overall, these results establish that PIV5-based HIV vaccine candidates are promising and warrant further investigation including moving on to primate challenge studies.
... This result suggested that V2 Abs contribute to protection against HIV-1 infection, although the protection mechanism remains unknown. Efforts to replicate the efficacy of the RV144 trial findings using similar vaccines in the setting of clade C immunogens in the HVTN 702 clinical trial failed to show differences in HIV acquisition between the vaccine and placebo arms (2). Thus, understanding the role of specific V2-directed envelope (Env) Abs in protection remains a crucial question. ...
The role of vaccine-induced anti-V2 Abs was tested in three protection experiments in rhesus macaques. In an experiment using immunogens similar to those in the RV144 vaccine trial (Anti-envelope [Env]), nine rhesus macaques were coimmunized with gp16092TH023 DNA and SIV gag and gp120A244 and gp120MN proteins. In two V2-focused experiments (Anti-V2 and Anti-V2 Mucosal), nine macaques in each group were immunized with V1V292TH023 DNA, V1V2A244 and V1V2CasaeA2 proteins, and cyclic V2CaseA2 peptide. DNA and protein immunogens, formulated in Adjuplex, were given at 0, 4, 12, and 20 weeks, followed by intrarectal SHIVBaL.P4 challenges. Peak plasma viral loads (PVL) of 106-107 copies/ml developed in all nine sham controls. Overall, PVL was undetectable in one third of immunized macaques, and two animals tightly controlled the virus with the Anti-V2 Mucosal vaccine strategy. In the Anti-Env study, Abs that captured or neutralized SHIVBaL.P4 inversely correlated with PVL. Conversely, no correlation with PVL was found in the Anti-V2 experiments with nonneutralizing plasma Abs that only captured virus weakly. Titers of Abs against eight V1V2 scaffolds and cyclic V2 peptides were comparable between controllers and noncontrollers as were Ab-dependent cellular cytotoxicity and Ab-dependent cell-mediated virus inhibition activities against SHIV-infected target cells and phagocytosis of gp120-coated beads. The Anti-Env experiment supports the role of vaccine-elicited neutralizing and nonneutralizing Abs in control of PVL. However, the two V2-focused experiments did not support a role for nonneutralizing V2 Abs alone in controlling PVL, as neither Ab-dependent cellular cytotoxicity, Ab-dependent cell-mediated virus inhibition, nor phagocytosis correlated inversely with heterologous SHIVBaL.P4 infection.
... Targeting HIV antigens to human CD40 and B-cell repertoire diversity prevention of HIV-1 infection [10][11][12]14]. However, the recent negative and disappointing results of the large Phase 3 HVTN 702 prophylactic trial put into question strategies aimed to elicit non-neutralizing anti-HIV antibodies and underscore the need to develop models for selecting candidate vaccines [31]. Although SIV challenge studies in NHPs are useful indicators for the advancement of vaccine candidates into clinical trials, they do not necessarily predict HIV-1 vaccine efficacy in humans [32]. ...
The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to efficiently transition from IgM B cells to IgG B cells. Here, we found that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mice. We further dissected hu-B cell responses directed against the HIV-1 Env protein elicited by targeting Env gp140 clade C to the CD40 receptor of antigen-presenting cells. The anti-CD40.Env gp140 vaccine was injected with CpG-B in a homologous prime/boost regimen or as a boost of a NYVAC-KC pox vector encoding Env gp140 clade C. Both regimens elicited Env-specific IgG-switched memory hu-B cells at a greater magnitude in hu-mice primed with NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific hu-B cells to express polyclonal IgG1 and IgG3 isotypes and a broad Ig VH/VL repertoire, with predominant VH3 family gene usage. These cells exhibited a higher rate of somatic hypermutation than the non-specific IgG ⁺ hu-B-cell counterpart. Both vaccine regimens induced splenic GC-like structures containing hu-B and hu-Tfh-like cells expressing PD-1 and BCL-6. We confirmed in this model that circulating ICOS ⁺ memory hu-Tfh cells correlated with the magnitude of gp140-specific B-cell responses. Finally, the NYVAC-KC heterologous prime led to a more diverse clonal expansion of specific hu-B cells. Thus, this study shows that CD40-targeted vaccination induces human IgG production in hu-mice and provides insights for the development of a CD40-targeting vaccine to prevent HIV-1 infection in humans.
... Unfortunately, the trial was stopped on 23 January 2020 following an interim analysis by an independent data and safety monitoring board (DSMB). The DSMB analysed data from 2694 vaccine recipients and 2689 placebo recipients and discovered that 129 HIV infections occurred among the vaccine recipients, and 123 HIV infections occurred among the placebo recipients (91,92). These findings indicated that the vaccine was not effective in preventing HIV infection and the DSMB recommended discontinuation of further vaccinations but allowed follow-up to continue. ...
Following the discovery of HIV as a causative agent of AIDS, the expectation was to rapidly develop a vaccine; but thirty years later, we still do not have a licensed vaccine. Progress has been hindered by the extensive genetic variability of HIV and our limited understanding of immune responses required to protect against HIV acquisition. Nonetheless, valuable knowledge accrued from numerous basic and translational science research studies and vaccine trials has provided insight into the structural biology of the virus, immunogen design and novel vaccine delivery systems that will likely constitute an effective vaccine. Furthermore, stakeholders now appreciate the daunting scientific challenges of developing an effective HIV vaccine, hence the increased advocacy for collaborative efforts among academic research scientists, governments, pharmaceutical industry, philanthropy, and regulatory entities. In this review, we highlight the history of HIV vaccine development efforts, highlighting major challenges and future directions.
... However, the recent trial HVTN702 in South Africa, based on the same modality of vaccination, was terminated because of lack of efficacy. 58 This trial utilized MF59 instead of Alum, and the difference in outcome was predicted in a preclinical SIV mac251 trial in RM that compared side by side the two adjuvants, supporting the different contributions of each vaccine adjuvant to the vaccine outcome and the need to test each variable independently. 59 Achievement of appropriate antibody responses, in particular neutralizing antibody, is considered the holy grail of the successful HIV vaccine [ 60-62 and references therein]. ...
Attempts to develop a protective HIV vaccine have had limited success, especially in terms of inducing protective antibodies capable of neutralizing different viral strains. As HIV transmission occurs mainly via mucosal surfaces, HIV replicates significantly in the gastrointestinal tract, and the oral route of vaccination is a convenient one to implement worldwide, we explored three SIV vaccine modalities administered orally and composed of SIV DNA priming with different boosting immunogens, with the goal of evaluating whether they could provide lasting humoral and cellular responses, including at mucosal surfaces that are sites of HIV entry. Twenty-four Cynomolgus macaques (CyM), were primed with replication-incompetent SIV DNA provirus and divided into three groups for the following booster vaccinations, all administered in the oral cavity: Group 1 with recombinant SIV gp140 and E. coli heat-labile toxin adjuvant dmLT, Group 2 with recombinant SIV-Oral Poliovirus (SIV-OPV), and Group 3 with recombinant SIV-MVA. Cell-mediated responses were measured using blood, lymph node, rectal and vaginal mononuclear cells. Significant levels of systemic and mucosal T-cell responses against Gag and Env were observed in all groups. Some SIV-specific plasma IgG, rectal and salivary IgA antibodies were generated, mainly in animals that received SIV DNA + SIV-MVA, but no vaginal IgA was detected. Susceptibility to infection after SIVmac251 challenge was similar in vaccinated and non-vaccinated animals, but acute infection viremia levels were lower in the group that received SIV DNA + SIV-MVA. Non-vaccinated CyM macaques maintained central memory and total CD4+ T cell levels in the normal range during the 5 months of post-infection follow-up as did the vaccinated animals, precluding evaluation of vaccine impact on disease progression. We conclude that the oral cavity vaccination tested in these regimens can stimulate cell-mediated immunity systemically and mucosally, but humoral response stimulation was limited with the doses and the vaccine platforms used.
... Optimum treatment regimens consist of a combination of two [2] or more antiretrovirals with a different mode of action, that allows the suppression of viremia to undetectable levels, giving a life-expectation comparable to uninfected people [3,4]. However, despite promising efforts, presently approved treatments do not allow immunization of people [5] or the eradication of the infection [6], requiring life-long treatment with optimal adherence. At the moment, only 64.6% of HIV-1 infected people are accessing antiretroviral therapy [1]. ...
HIV-1 infection requires life-long treatment and with 2.1 million new infections/year, faces the challenge of an increased rate of transmitted drug-resistant mutations. Therefore, a constant and timely effort is needed to identify new HIV-1 inhibitors active against drug-resistant variants. The ribonuclease H (RNase H) activity of HIV-1 reverse transcriptase (RT) is a very promising target, but to date, still lacks an efficient inhibitor. Here, we characterize the mode of action of N’-(2-hydroxy-benzylidene)-3,4,5-trihydroxybenzoylhydrazone (compound 13), an N-acylhydrazone derivative that inhibited viral replication (EC50 = 10 µM), while retaining full potency against the NNRTI-resistant double mutant K103N-Y181C virus. Time-of-addition and biochemical assays showed that compound 13 targeted the reverse-transcription step in cell-based assays and inhibited the RT-associated RNase H function, being >20-fold less potent against the RT polymerase activity. Docking calculations revealed that compound 13 binds within the RNase H domain in a position different from other selective RNase H inhibitors; site-directed mutagenesis studies revealed interactions with conserved amino acid within the RNase H domain, suggesting that compound 13 can be taken as starting point to generate a new series of more potent RNase H selective inhibitors active against circulating drug-resistant variants.
... The recent abandonment (due to futility) of the latest HIV-1 vaccine efficacy trial, HVTN-702, increases the emphasis on immunization strategies for inducing broadly neutralizing antibodies (bNAbs) (Cohen, 2020). HIV-1 envelope (Env) glycoproteins are the basis of many vaccine-development strategies, particularly those for eliciting bNAbs. ...
Recombinant HIV-1 envelope (Env) glycoproteins of ever-increasing sophistication have been evaluated as vaccine candidates for over 30 years. Structurally defined mimics of native trimeric Env glycoproteins (e.g., SOSIP trimers) present multiple epitopes for broadly neutralizing antibodies (bNAbs) and their germline precursors, but elicitation of bNAbs remains elusive. Here, we argue that the interactions between Env and the immune system render it exceptional among viral vaccine antigens and hinder its immunogenicity in absolute and comparative terms. In other words, Env binds to CD4 on key immune cells and transduces signals that can compromise their function. Moreover, the extensive array of oligomannose glycans on Env shields peptidic B cell epitopes, impedes the presentation of T helper cell epitopes, and attracts mannose binding proteins, which could affect the antibody response. We suggest lines of research for assessing how to overcome obstacles that the exceptional features of Env impose on the creation of a successful HIV-1 vaccine.
The human immunodeficiency virus (HIV) continues to pose a significant global health challenge, with millions of people affected and new cases emerging each year. While various treatment and prevention methods exist, including antiretroviral therapy and non-vaccine approaches, developing an effective vaccine remains the most crucial and cost-effective solution to combating the HIV epidemic. Despite significant advancements in HIV research, the HIV vaccine field has faced numerous challenges, and only one clinical trial has demonstrated a modest level of efficacy. This review delves into the history of HIV vaccines and the current efforts in HIV prevention, emphasizing pre-clinical vaccine development using the non-human primate model (NHP) of HIV infection. NHP models offer valuable insights into potential preventive strategies for combating HIV, and they play a vital role in informing and guiding the development of novel vaccine candidates before they can proceed to human clinical trials.
HIV affects more than 38 million people worldwide. Although HIV can be effectively treated by lifelong combination antiretroviral therapy, only a handful of patients have been cured. Therapeutic vaccines that induce robust de novo immune responses targeting HIV proteins and latent reservoirs will likely be integral for functional HIV cure. Our study shows that immunization of naïve rhesus macaques with arenavirus-derived vaccine vectors encoding simian immunodeficiency virus (SIV SME543 Gag, Env, and Pol) immunogens is safe, immunogenic, and efficacious. Immunization induced robust SIV-specific CD8 ⁺ and CD4 ⁺ T-cell responses with expanded cellular breadth, polyfunctionality, and Env-binding antibodies with antibody-dependent cellular cytotoxicity. Vaccinated animals had significant reductions in median SIV viral load (1.45-log 10 copies/mL) after SIV MAC251 challenge compared with placebo. Peak viral control correlated with the breadth of Gag-specific T cells and tier 1 neutralizing antibodies. These results support clinical investigation of arenavirus-based vectors as a central component of therapeutic vaccination for HIV cure.
A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic and viral RNase H inhibitory activity. Several compounds showed considerable activity against Toxoplasma gondii parasites and Leishmania major amastigotes, which warrants further investigation. Based on the structural similarities of certain derivatives with common viral RNase H inhibitors, a HIV-1 RNase H assay was used to study the RNase H inhibition by selected test compounds. Docking of active derivatives into the active site of the HIV-1 RNase H enzyme was carried out. The new compound 2a, inactive in the antiparasitic tests, showed distinct HIV-1 RNase H inhibition. Thus, ring substitution determines antiparasitic or HIV-1 RNase H inhibitory activity of this promising compound class.
The advanced-phase HIV prevention vaccine trials done in South Africa (HVTN 702) and in Thailand (RV144), which both investigated canarypox vectors and adjuvanted gp120 proteins, gave rise to different results. The South African trial did not find vaccine efficacy, whereas the Thai trial had modest, but statistically significant, success with the modified intention-to-treat analysis prespecified in the protocols of both studies. An understanding of the differences between the studies is required to avoid the possible, but erroneous, conclusion that the results from the South African trial negatively affect the results of the Thai trial.
The bioactive components of Garcinia indica, garcinol (camboginol), and isogarcinol (cambogin), are suitable drug candidates for the treatment of various human diseases. HIV-1-RNase H assay was used to study the RNase H inhibition by garcinol and isogarcinol. Docking of garcinol into the active site of the enzyme was carried out to rationalize the difference in activities between the two compounds. Garcinol showed higher HIV-1-RNase H inhibition than the known inhibitor RDS1759 and retained full potency against the RNase H of a drug-resistant HIV-1 reverse transcriptase form. Isogarcinol was distinctly less active than garcinol, indicating the importance of the enolizable β-diketone moiety of garcinol for anti-RNase H activity. Docking calculations confirmed these findings and suggested this moiety to be involved in the chelation of metal ions of the active site. On the basis of its HIV-1 reverse transcriptase-associated RNase H inhibitory activity, garcinol is worth being further explored concerning its potential as a cost-effective treatment for HIV patients.
Bioisosteric replacement and scaffold hopping are powerful strategies in drug design useful for rationally modifying a hit compound towards novel lead therapeutic agents. Recently, we reported a series of thienopyrimidinones that compromise dynamics at the p66/p51 HIV-1 reverse transcriptase (RT)-associated Ribonuclease H (RNase H) dimer interface, thereby allosterically interrupting catalysis by altering the active site geometry. Although they exhibited good submicromolar activity, the isosteric replacement of the thiophene ring, a potential toxicophore, is warranted. Thus, in this article, the most active 2-(3,4-dihydroxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one 1 was selected as the hit scaffold and several isosteric substitutions of the thiophene ring were performed. A novel series of highly active RNase H allosteric quinazolinone inhibitors was thus obtained. To determine their target selectivity, they were tested against RT-associated RNA-dependent DNA polymerase (RDDP) and integrase (IN). Interestingly, none of the compounds were particularly active on (RDDP) but many displayed micromolar to submicromolar activity against IN.
Background:
Pre-exposure prophylaxis (PrEP) with Tenofovir Disoproxil Fumarate and Emtricitabine (TDF-FTC) has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical "placebo arm" for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network (HPTN) 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP.
Methods:
Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study (VOICE).
Results:
Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over one year of follow-up in the placebo groups of four completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% CI 3.2-4.2) among HPTN 082 participants in the absence of PrEP and other risk reduction interventions.
Conclusions:
We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.
Mathematical immunology is the branch of mathematics dealing with the application of mathematical methods and computational algorithms to explore the structure, dynamics, organization and regulation of the immune system in health and disease. We review the conceptual and mathematical foundation of modelling in immunology formulated by Guri I. Marchuk. The current frontier studies concerning the development of multiscale multiphysics integrative models of the immune system are presented.
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