by Ekaterina Taneva
Historically, vaccines have been the most effective tools for the eradication of infectious diseases. Although an HIV vaccine remains a high global health priority, and despite the substantial effort and funding invested by the NIAID’s Vaccine Research Center, industry, non-profit organizations and volunteer groups, there is no effective HIV vaccine yet. Nonetheless, the claims, hypotheses, speculations and analyses propounded by the media have piqued the public interest in HIV vaccine research. Consequently, unrealistic hopes for an HIV-free world have been raised or alternatively dampened by disappointing clinical trial results. Currently, improved vaccines based on broadly neutralizing anti-HIV antibodies are advancing in the pipeline, and new HIV targets are being identified, thus fueling optimism with regards to the feasibility of this ultimate HIV extermination modality (1, 2, 3). Considering the obstacles of eliciting broadly functional antibody responses, recent research has shifted towards studying T-cell mediated immunity to determine whether CD8+ T cells can inhibit viral replication after infection, thus serving as an “intermediate step” until immunogens that induce broadly protective antibodies are characterized (2). Dissection of the mechanism of cellular immune response to HIV with regards to the balance between CD4+ and CD8+ T cells, polyfunctionality, avidity, specificity, kinetics, location, and regulation of the immune response are necessary to optimize current vaccine strategies (2).
So what are the barriers to successful HIV vaccine development? One of the hurdles stems from HIV’s “unprecedented” variability driven by the host’s “immune pressure” and also by the high rate of recombination (3), which could be overcome by developing broadly neutralizing antibodies. However, such an approach is limited by unwanted cross-reactivity with host proteins. Therefore, the line between desiring a specific versus a broad response is thin and controversial. In addition to the remarkable “hypervariability” of the virus, other factors limiting to vaccine development include the lack of extensive knowledge on the natural human immune response to HIV as well as the challenges posed by differences in the immunogenetics between the animals used for efficacy studies and humans. For these reasons, research on innate immunity against HIV is also accompanied by efforts to develop new and/or optimize existing animal models for studying viral infection and replication that would provide more valid bases for human trials.
Significant publicity has been given to the safe and partially successful HIV vaccine trial in Thailand. The RV144 trial reported an overall 31.2% decrease in the rate of HIV infection among vaccinated individuals, thus demonstrating that an HIV vaccine is within reach, and not just a distant hope of scientists and patients combined (4). Despite the so-called “renaissance” in the HIV vaccine field, one cannot help but wonder if partial protection necessarily equates to success, and if building upon partially encouraging data will actually lead to a solid solution of the puzzle of HIV’s immunoevasive strategies. The few successful steps taken recently may not be substantial enough to overshadow the disappointment from failed clinical trials (5, 6). In both the STEP and the Phambili clinical trials, it was found that vaccine recipients were significantly more likely to get infected with HIV. Although a stringent statistical analysis could not be performed, there was a trend toward a greater number of vaccinated individuals who became infected compared with the patients on placebo injections (1, 2). The evidence that experimental HIV vaccines may increase the chance of HIV infection was discussed on October 10th at the AIDS Vaccine 2012 Conference in Barcelona, Spain (7). The results are still confusing, and there are speculations that vaccine administration might have increased T cell activation at sites of HIV infection, thus shifting the balance from protection to infection. However, such assumptions are not validated, and re-analysis of the disappointing clinical data is ongoing. It is likely that engagement in risky sexual behavior and lack of circumcision among vaccinated male patients may have contributed to the disappointing outcomes. Other confounding factors, such as herpes virus co-infection among HIV-infected individuals, were recently identified (2).
Despite the incorporation of knowledge from diverse fields, such as HIV immunology, systems biology, vector genetics, peptide chemistry, structural biology, adjuvant development and antigen delivery, no candidate in clinical development has sufficiently controlled HIV infection and viral replication (3). This raises a painful question posed not exclusively by scientists but also by patients with regards to the feasibility, safety and efficacy of such an approach. Questioning the concept of vaccines is not uncommon, especially after many clinical trials report not only lack of efficacy but higher rates of infection among vaccine recipients (3, 4, and 5). Such outcomes widen even the already existing clash between patients and scientists over the safety and efficacy of vaccines, and fuel the disbelief and discouragement experienced by the public (7). The disappointing clinical trial data leaves unanswered questions bothering scientists engaged in HIV research:
- Were the unsuccessful clinical trials merely cases of failure of a specific product because they did not induce an immune response of sufficient quality and quantity, or were they failures of a concept?
- Are T-cell based vaccines or vaccines based on broadly neutralizing antibodies, or a combination of both, the answer?
- What are the best animal models to be used for pre-clinical studies, or are animals too different in their infection kinetics and immune biology to provide any substantial evidence of efficacy before a human trial?
- What is the best way to invigorate and advance HIV vaccine research without initiating expectations that may later turn out to be unfounded?
The answer to such questions may lie in building upon observations acquired from failed trials, and acceleration of current research strategies with excitement but also caution.
- Gray et al. “Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study “ Lancet Infect Dis. 11 (7) (2011): 504-507
- Fauci, A. S. “HIV Vaccine Research: The Way Forward” Science 321 (2008): 530-532
- Koff, W. et al. “Accelerating the development of a safe and effective HIV vaccine: HIV vaccine case study for the Decade of Vaccines” Vaccine 31S (2013): B204-B208
Ekaterina is a 3rd year PhD student in Microbiology & Immunology and Pediatrics. She is interested in HIV, HSV, antiviral drug pharmacology, clinical and translational research, and women’s health.