The Quest for the HIV Vaccine: Are We Closer Than We Think?

January 20, 2016

HIVBy Amar Parikh, MD 

Peer Reviewed

Amidst the global panic over the recent Ebola outbreak, another well-known pathogen that has been devastating the world for decades continues to smolder—the human immunodeficiency virus (HIV). According to the World Health Organization (WHO), in 2013 there were 35 million people worldwide living with HIV, 2.1 million of who were newly infected that year [1]. HIV/AIDS has claimed the lives of nearly 40 million people to date, with 1.5 million people dying from AIDS in 2013 alone. Although highly active antiretroviral therapy (HAART) has been remarkably successful, it is not a cure for HIV infection. The failure to cure HIV/AIDS is due to the reservoir of latently infected T cells formed in the acute phase of the infection that re-establish virus loads upon treatment interruption [2]. The use of HAART as treatment and prophylaxis, the practice of male circumcision of high-risk individuals, increased public awareness of safer sex practices, and the expansion of clean needle programs have all lead to decreased HIV transmission rates. However, infection statistics from the United Nations remain sobering: for every 1 person who began treatment for HIV last year, 1.3 people were newly infected [3, 4, 5]. As such, the development of an effective vaccine against HIV remains one of the most pressing priorities for the medical community. Results from recent clinical trials and advances in basic science research are encouraging, and suggest that a successful HIV vaccine may not be far away.

RV 144 – A Glimmer of Hope

The general principle underlying vaccination is to isolate the pathogen, inactivate or weaken it, and then inject it into the body so the immune system can mount an antigen-specific response without an actual infection. Applying this concept to HIV has been difficult, as its genetic diversity and ability to rapidly mutate have presented formidable challenges. To date, scientists have conducted over 250 HIV vaccine clinical trials, most without much success.

The tides began to turn in 2009, when the world’s largest HIV vaccine trial was conducted in Thailand [6]. The Phase III study, referred to as RV 144 or the “Thai trial,” involved more than 16,000 participants (aged 18 to 30) who received either placebo or a “prime-boost” vaccination regimen. The regimen consisted of 4 priming injections with a recombinant canary pox vector vaccine (ALVAC-HIV [vCP1521]), followed by 2 booster injections with a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccines were based on HIV clades B and E, the most common subtypes of HIV found in Thailand. After the 3-year follow-up period, the investigators found that people who received the vaccine series were 31% less likely to contract HIV than those given placebo. While the RV 144 vaccine regimen did not affect viral loads or CD4+ counts among patients who did contract HIV, the partial protection attributed to the vaccine warranted further investigation.

Of note, the RV 144 vaccine regimen’s ability to protect against HIV was most evident soon after vaccination and waned over time. The  potential for an early, robust immune response suggested that the addition of late boosters could prolong efficacy. Furthermore, an immune-correlates analysis determined how the RV144 vaccine modulated T cell, IgG antibody, and IgA antibody responses and whether these responses were related to infection risk [7]. The authors found that the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-envelope proteins (Env) was inversely associated with the rate of infection, while the binding of IgA antibodies to Env was directly correlated with the rate of infection. These results suggested that V1V2 IgG antibodies might contribute to protection against HIV, whereas high levels of Env-specific IgA antibodies may reduce the effectiveness of protective antibodies. Taken together, a vaccine engineered to induce higher levels of V1V2 IgG antibodies and lower levels of Env-specific IgA antibodies than the RV144 vaccine may provide enhanced efficacy.

Forging Ahead in South Africa

Building on the success of the RV 144 study, a pilot study called the HVTN 097 trial was carried out in South Africa. The preliminary results of this study were presented at the HIV Research for Prevention conference in Cape Town, South Africa in late October, 2014 [8]. HVTN 097 was a small Phase I trial conducted to ascertain whether the vaccine regimen tested in Thailand would safely induce a similar immune response profile in South Africans. It did not evaluate the effectiveness of the vaccine in preventing HIV acquisition, rather it sought to establish proof of concept as to whether the RV 144 results could be reproduced in a geographically distinct patient population [9]. The trial employed the same primer and booster vaccines from RV 144 and was tested among 100 healthy adults in South Africa. Immune responses were measured 2 weeks after the last immunization by quantifying the number of HIV-Env-specific T-cells expressing IFN-y and/or IL-2. The RV 144 regimen was well tolerated and induced an immune response similar to, if not better than, that seen in the original Thai trial. Immunogenicity of RV 144 was detected, regardless of age, gender, or BMI, a critical observation as these factors have previously been shown to impact immune responses to HIV vaccines.

In January 2015, Phase 1 and Phase 2 trials were started using a modified form of the vaccine specifically tailored to the subtype of HIV most commonly found in South Africa, clade C. In the future, researchers plan to add a protein adjuvant to augment the immune response. Furthermore, since the RV 144 trial demonstrated waning protection beyond the initial immune response, an additional booster vaccination will be added at 12 months. This efficacy trial is expected to enroll approximately 7,000 participants, and results are to be released in 2018 [10]. If the trials are successful, a vaccine product could be taken to licensure as early as 2019, according to lead investigator, Glenda Gray [10]. It is worth noting, however, that while the success of the RV 144 trial and the early results from South Africa have been promising, the implementation of regional, clade-specific vaccines would be a logistical challenge, as it would require the development, approval, and worldwide distribution of multiple vaccines tailored to the local HIV strains of each region. 

Back to the Bench – Broadening the Range of HIV Vaccines

In Seattle, Washington, researchers have made a discovery that could fundamentally alter the way we attack HIV. To date, one of the main obstacles to creating an effective HIV vaccine is that vaccines typically elicit antibodies against only a narrow range of existing HIV-1 strains. In a recent study published in Science, McGuire et al found that immunogenic proteins derived from the envelope glycoprotein of HIV-1 preferentially activated B-cells to produce narrow neutralizing antibodies (nNAbs) rather than stimulating broadly neutralizing antibodies (bNAbs) that would provide protection against a wide range of strains [11]. Since most HIV vaccines consist of proteins derived from the HIV-1 envelope glycoprotein, this could explain why vaccines thus far have been ineffective. To overcome this limitation, the investigators developed a recombinant form of HIV envelope-derived glycoproteins that preferentially activated the B-cells to produce bNAbs instead of nNAbs. They also showed that the recombinant immunogenic proteins could induce production of bNAbs in patients prior to any exposure to HIV, thus potentially serving as the basis for an effective vaccine . Another strategy that is being investigated is the use of sequence information from multiple circulating virus strains to design a composite HIV-1 vaccine based on these “mosaic” sequences. It has been shown that broader cellular and humoral immune responses are induced by mosaic antigen sequences as compared to conventional wild-type HIV antigens [12]. Barouch et al investigated the effects of mosaic vaccines in rhesus monkeys, and found that the vaccines reduced the risk of acquiring simian-HIV per exposure by 90% [13]. The ability of the mosaic vaccine to induce significant protection against a highly potent form of the SIV virus in simian subjects suggests that it may also be effective against highly pathogenic HIV strains in human trials.

A New Era

While the medical community has made significant strides, the global threat posed by HIV underscores the urgent need for an effective vaccine to curtail this pandemic. The results from the vaccine trials highlighted above are therefore all the more exciting, and the eyes of the world will be on South Africa as the next phase of these studies rolls out. Recent advances in the laboratory also suggest that a vaccine candidate that induces bNAbs or utilizes mosaic sequences could potentially be added to the vaccine regimens currently being tested for combined efficacy. All in all, advances in HIV vaccinology may spawn a new era in our fight against this devastating virus, and make the idea of a world without HIV/AIDS seem more of a tangible reality than an idyllic dream.

Dr. Amar Parikh is a 2nd year  resident at NYU Langone Medical Center.

Peer reviewed by Thomas Norton, MD, Assistant Professor in the Division of Infectious Diseases at the NYU School of Medicine

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