Despite the disappointing results of the STEP study, several key lessons have already been learned. First, it is clear that the path forward towards an HIV-1 vaccine will be neither simple nor straightforward. Second, the importance of understanding both systemic and mucosal immune responses to vaccine vectors is paramount. Third, the biological determinants of HIV-1 acquisition and the impact that vector-specific and antigen-specific mucosal immune responses may have on this process will require intensive investigation. Fourth, clinical vaccine studies will need to adapt to the safety concerns raised by the STEP study, such as possibly excluding subjects who have pre-existing NAbs to the vaccine vector that is utilized until this phenomenon is more completely understood. Fifth, future T cell based vaccine candidates should be prioritized for clinical efficacy studies only if they are convincingly superior to the homologous rAd5-Gag/Pol/Nef regimen that has failed. Sixth, nonhuman primate challenge models should be recalibrated based on the STEP study to help guide future vaccine development.
The protection afforded by the homologous rAd5 regimen against SHIV-89.6P indicates that this model lacks sufficient stringency for the evaluation of T cell based vaccine candidates. Although the more stringent SIV challenge model cannot be considered to be validated until there is a successful clinical efficacy study in humans, it seems reasonable to utilize SIVmac239 or SIVmac251 as challenge viruses for evaluating next generation vaccine candidates (Box 3
). Preclinical challenge studies need to be adequately powered with sufficient follow-up time, and the vaccine schedule and dose should model the proposed clinical regimen. For optimal stringency, studies should exclude rhesus monkeys that express MHC class I alleles that are specifically associated with efficient virologic control, such as Mamu-A*01, Mamu-B*17, and Mamu-B*08. The use of homologous Env antigens that may inappropriately overestimate protective efficacy should also be avoided. Mucosal challenges may offer certain physiologic advantages over intravenous challenges, and these challenge models should therefore be developed. Finally, increased emphasis should be placed on assessing the capacity of promising vaccine candidates to protect against highly heterologous SIV challenges, since infecting viruses in humans will almost certainly be heterologous to any vaccine sequence. Since very few heterologous SIV challenge studies have been performed to date, a practical approach may be to determine the protective efficacy of promising vaccine candidates against both homologous and heterologous SIV challenges. It is currently debated whether nonhuman primate challenge studies should be utilized as a formal “gatekeeper” for advancing vaccine candidates into clinical efficacy studies, since the capacity of this model to predict the results of clinical efficacy studies remains unclear. Nevertheless, it would seem reasonable to give a relative priority to develop vaccine candidates that lead to durable control of setpoint viral loads following SIV challenge.
Box 3. Recommendations for Preclinical Challenge Studies of T Cell Based Vaccines
- Utilize stringent challenge virus (SIVmac239, SIVmac251)
- Design study with adequate power and follow-up time
- Model clinical regimen with vaccine schedule and dose
- Select rhesus monkeys that lack MHC alleles associated with efficient virologic control (Mamu-A*01, B*17, B*08)
- Avoid the use of a homologous Env antigen
- Assess promising vaccine concepts against both homologous and heterologous viral challenges
The STEP study has had a major impact on other HIV-1 vaccine programs in the field. HVTN 503 was terminated as it utilized the same rAd5 based vaccine candidate that was utilized in HVTN 502. The NIH Vaccine Research Center has developed a DNA prime, rAd5 boost vaccine regimen expressing clade B Gag-Pol and multiclade Env antigens. This vaccine candidate has been shown to be immunogenic in the majority of individuals in phase 1 studies, particularly for the Env antigens62, 68, 83
. In preclinical studies, a DNA prime, rAd5 boost vaccine regimen expressing SIV Gag, Pol, Nef, and Env antigens afforded a 1.1 log reduction of peak viral loads for 112 days following a homologous SIVmac251 challenge77
. No durable control of setpoint viral loads was observed with this vaccine, although delayed progression to AIDS-related mortality was evident77
. NIAID recently announced that it will not proceed with a large phase 2b efficacy study known as PAVE 100, although a smaller, more focused efficacy study with this vaccine candidate is still under consideration84
. DNA prime, poxvirus boost regimens are also being evaluated utilizing MVA69
vectors, and phase 1 clinical trials have demonstrated immunogenicity in the majority of volunteers. Central to all of these programs, however, is the hypothesis that DNA priming prior to vector boosting will improve protective efficacy. This has been observed in some72
but not all77
SIV challenge studies, and thus it still remains an open question that requires further investigation and should be considered a high priority.
Novel rAd vectors derived from Ad serotypes that are rare in human populations are also being explored as a strategy to evade pre-existing Ad5-specific NAbs. It is hoped that such vectors may offer immunologic as well as safety advantages as compared with rAd5 vectors by circumventing pre-existing vector-specific NAbs. However, these possibilities have not yet been confirmed in clinical trials. Current strategies include the development of rare serotype rAd26, rAd35, and rAd48 vectors78, 79, 85
; chimeric rAd5HVR48 vectors in which dominant Ad5-specific NAb epitopes have been exchanged86
; and non-human rAd vectors87, 88
. Rare serotype rAd vectors are biologically different from rAd5 vectors in terms of their cellular receptors, tropism, intracellular trafficking pathways, and innate immune profiles. Moreover, rAd26 and rAd48 vectors elicit T lymphocyte responses of a substantially different phenotype as compared with rAd5 vectors89
, and potent heterologous rAd prime-boost regimens can be constructed utilizing serologically distinct rAd vectors. We have recently demonstrated that a heterologous rAd26 prime, rAd5 boost regimen expressing SIV Gag afforded a durable 2.4 log reduction of setpoint viral loads following SIVmac251 challenge of Mamu-A*01-negative rhesus monkeys, whereas a homologous rAd5 regimen provided no protection in this stringent challenge model (D. Barouch, unpublished data). These data suggest that vaccine candidates that elicit improved magnitude, breadth, and quality of T lymphocyte responses may provide superior protective efficacy as compared with homologous rAd5 regimens.