HIV vaccine
For microbiologic aspects of the causative organism(s), see Human Immunodeficiency Virus (HIV)  For clinical aspects of this desease, see HIV

# Overview
HIV infection is a major global health issue, affecting 36.7 million people worldwide. The number of people living with HIV on antiretroviral therapy (ART) reached 17 million in 2015. Although ART has dramatically reduced morbidity and mortality in individuals with HIV infection and can also prevent HIV transmission but it cannot eradicate HIV infection due to the persistence of a latent viral reservoir, hence the need for antiretroviral therapy ART is lifelong and the cost is substantial. Although antiretroviral therapy ART is highly efficacious in preventing transmission in the setting of mother to child transmission, in sexual transmission through the treatment of infected partners in relationships, through pre-exposure or or post-exposure prophylaxis, but all these scale-up difficulties and costs may make widespread implementation challenging. Thus an HIV vaccine is essential as it is a more sustainable solution.The development of a universal effective HIV vaccine is an exceptionally difficult biomedical challenge. Firstly, no case of natural eradication of HIV infection has been identified, thus mechanisms of protection have not been definitively established. Secondly, the extreme diversity of HIV is a major obstacle as strains belonging to different subtypes can differ by up to 35% in their envelope (Env) proteins.Thus, vaccine immunogens derived from a particular strain may not be effective against other strain. To generate an efficacious global vaccine, immunogens capable of generating protective responses covering most major strains are required.

# Historical Perspective
- Ever since HIV was formally identified as the cause of AIDS, there have been ongoing efforts on vaccines against the disease.
- On April 24, 1984, the US Secretary of Health and Human Services, Margaret Heckler, announced that vaccines will be researched and made ready for preliminary testing by the year 1986.
- Traditional approaches of using live attenuated or whole inactivated viruses were considered unsafe because of the risk of permanently integrating proviral DNA within host chromosomes.
- Advancements in vaccine development had to wait until mid-1980's when recombinant DNA technologies were becoming available for research applications.
- Following the success of recombinant Hepatitis B vaccine, recombinant DNA technologies were also being researched for HIV vaccines.
- All these efforts came to a standstill with growing knowledge about extreme mutability and immune evasion mechanisms of existing HIV strains.
- It was further complicated by the fact that neutralizing antibodies had no protective effects and their titers were similar among asymptomatic carriers and patients with active disease. 

# Clinical trials for HIV vaccine
The 6 HIV-1 vaccine efficacy trials done to date, to delineate potential protective responses, and to explore new vaccine candidates that are currently being developed are as follows.

## VAX003 and 004
- VAX003 was a double-blind, randomized trial of AIDSVAX B/E (a bivalent vaccine composed of  recombinant gp120 from subtype B, strain MN and subtype CRF01_AE, strain A244) in injection drug users (IDU) in Thailand.
- VAX004 was a double-blind, randomized trial of AIDSVAX B/B (a bivalent vaccine composed of subtype B rgp120 from strains MN and GNE8) conducted among men who have sex with men (MSM) and women at high risk for heterosexual transmission of HIV-1 in North America and The Netherlands.
- Despite the development of anti-glyco-proteins 120 antibody responses, both vaccines did not demonstrate protection.
- The disappointing results from the VAX003 and VAX004 trials and data supporting the importance of cell mediated immunity in controlling viral replication in rhesus macaques and human elite controllers,attention turned to the use of T-cell vaccines to induce HIV-specific cellular immune responses.  

## STEP and Phambili studies
- The STEP study was a double-blind, randomized trial of the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals at high risk of HIV-1 acquisition in the Americas, Caribbean and Australia. 
- The Phambili study was a double-blind, randomized trial designed to evaluate the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals in South Africa where HIV clade C is predominant. This study was halted following the Step study's interim analysis and subsequent analysis also found no efficacy.

## RV144
- RV144 was a randomized, double-blind trial that evaluated 4 priming injections of ALVAC-HIV , recombinant canarypox vector expressing HIV-1 Gag and Pro (subtype B LAI strain) and CRF01_AE (subtype E) HIV-1 gp120 (92TH023) linked to the transmembrane anchoring portion of gp41 (LAI) plus 2 booster injections, AIDSVAX B/E (bivalent HIV-1 gp120 subunit vaccine containing a subtype E Env from strain A244 (CM244) and a subtype B Env from strain MN), co-formulated with alum.
- The rationale for the prime boost strategy was to induce both cellular and humoral responses.
- The RV144 trial was the only efficacy trial to date that demonstrated efficacy.

## HVTN 505
- The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, placebo-controlled trial of a prime boost, DNA/rAd5 vaccine consisting of a 6-plasmid DNA vaccine. 
- The vaccine induced both cellular and humoral responses. However, these were not associated with protection.

## Conclusions
- None of the vaccine candidates that have completed efficacy trials to date induced strong broadly neutralizing antibodies (bnAb) responses.
- CD8+ T cell responses were induced in STEP, Phambili and HVTN505 studies but were not associated with protection.
- Only one trial, RV144 demonstrated efficacy and protection was associated with functional binding antibodies. However, efficacy was of suboptimal magnitude and was not durable.

# Broadly neutralizing antibodies
- They are antibodies capable of neutralizing diverse circulating strains from multiple clade groups, can be present in 2030% of individuals with HIV-1 infection.
- They usually develop 24 years after HIV-1 infection, in the presence of continual antigen stimulation from viral replication.
- HIV envelope protein, composed of gp120 and  gp41 monomers, is the main target for broadly neutralizing antibodies. 

## Passive immunization using broadly neutralizing antibodies
- The efficacy of broadly neutralizing antibodies as passive immunotherapy has been demonstrated in Rhesus monkey models.
- A single infusion of broadly neutralizing antibody can prevent infection from a single high-dose Simian/Human Immunodeficiency Virus (SHIV) challenge.
- The use of broadly neutralizing antibodies as passive immunotherapy in its current form will be challenging to implement widely, due to the production costs, the healthcare infrastructures necessary for infusions and the need for repeated administrations.
- New research is taking place to explore the introduction of broadly neutralizing antibodies(bnAb) using vectored immunoprophylaxis, where adeno-associated virus (AAV) vectors are used to deliver the genes encoding broadly neutralizing antibodies to muscle tissues, thereby enabling long-term production and systemic distribution. This technique has been shown to protect humanized mice as well as rhesus monkey against high dose intravenous and repeated mucosal challenges.

## Eliciting broadly neutralizing antibodies through immunization
- An immunogen that can elicit broadly neutralizing antibodies (bnAb) responses has still not been identified and the high levels of somatic mutations in bnAb suggest complex maturation pathways.
- The SOSIP gp140 trimer is a mimic of the natural envelope (Env) trimer, where the gp120-gp41 interactions are stabilized by an intermolecular disulfide bond, and the gp41-gp41 interactions are stabilized by an isoleucine-to-proline substitution at position 559 in the N-terminal heptad repeat region of gp41.
- Immunization with SOSIP trimers induced neutralizing antibodies in rabbits and to a lesser extent in Rhesus monkeys but broadly neutralizing antibody responses were not generated.

## CD4 Binding Site Antibodies
- The virus entry into targeted cells is dependent on viral attachment to the CD4 receptor and is mediated through binding to a conformational epitope on the trimeric envelop glycoprotein termed the CD4 binding site (CD4bs).
- Any antibody that is specific to CD4 binding sites can block the entry of virus into the cell.
- Many such antibodies have now been isolated from human donors, and they share common features, such as heavy chain mimicry of the CD4 receptor.
- One of first CD4 biniding site antibodies that was isolated from human infected individual that had been living with untreated infection for over 15 years is VRC01.
- A study demonstrated that VRC01 neutralized 91% of pseudovirions at a half maximal inhibitory concentration (IC50) of <50 g/ml, and neutralized 72% of primary isolates at an IC50 of <1 g/ml.

# Mosaic vaccine
- All the HIV-1 vaccines that have progressed to efficacy trials to date have predominantly been regional and clade-specific.
- The goal of mosaic HIV-1 vaccine is to generate immune responses that cover the diverse spectrum of circulating HIV-1 isolates, potentially resulting in a single vaccine that can be rolled out globally.
- Mosaic HIV-1 antigens delivered by replication-incompetent Ad26 vectors or DNA prime-recombinant vaccinia boost regimens have been shown to augment both the breadth and depth of antigen-specific T cell responses when compared with consensus or natural sequence HIV-1 antigens in Rhesus monkeys.

# T-cell based vaccine concepts
- Most current vaccine concepts aim at inducing antibody responses in the context of appropriate CD4+ T-cell help, while pure CD8+ T-cell approaches have mostly fallen out of favor. Nevertheless, a couple of promising T-cell focused approaches have been developed over the last years, and are scheduled to move into phase 1 trials in the near future.
- One immunogen, based on a CMV vector, has consistently led to complete control of virus replication in 5060% of animals in non-human primate challenge studies.
- The vector used in these studies was based on attenuated Rhesus CMV; whether these interesting immunological features will translate to clinical trials using a human CMV vector remains to be determined.
- Recent advances in T cell based vaccines have focused on incorporating the near complete gene sequences of several proteins expressed by the viral strains in HIV controllers. These composite immunogens aim at maximizing the incorporation of variable viral epitopes.
- In a study among rhesus monkeys, it was observed that the mosaic antigens incorporating several phenotypes of HIV-1 Gag, Pol, and Env antigens administered through replication-incompetent adenovirus serotype 26 vectors markedly increased the depth and breadth of T lymphocyte responses.

# Conclusion
- Developing an HIV vaccine is a challenge due to global HIV-1 diversity and the difficulties in inducing protective antibody responses and cellular immune responses.
- One of the major hurdles for the HIV vaccine field has been the lack of a fully predictive animal model. New humanized mouse models may provide a unique preclinical framework for testing the induction of broadly neutralizing antibodies.
- The past few years have seen an explosion in the depth of knowledge and number of new potential approaches to generating an effective HIV vaccine, and each new idea has promising concepts in the pipeline aimed at achieving its goals.