US Military HIV Research Program, Walter Reed Army Institute of Research, Bethesda, Maryland, USA.
Address correspondence to: Nelson L. Michael, US Military HIV Research Program, Walter Reed Army Institute of Research, 6720-B Rockledge Drive, Suite 400, Bethesda, Maryland 20817, USA. Phone: 301.500.3601; Fax: 301.500.3666; E-mail: email@example.com.
First published December 27, 2011 - More info
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Human adenoviral vectors are being developed for use in candidate vaccines for HIV-1 and other pathogens. However, this approach suffered a setback when an HIV-1 vaccine using an adenovirus type 5 (Ad5) vector failed to reduce, and might even have increased, the rate of HIV infection in men who were uncircumcised and who had preexisting antibodies specific for Ad5. This increased interest in the evaluation of serologically distinct adenoviral vectors. In this issue of the JCI, Frahm and coworkers report evidence that preexisting cellular immune responses directed toward Ad5 reduce the immunogenicity of antigens expressed in Ad5-vectored vaccines and have cross-reacting potential with non-Ad5 adenoviral vectors. The implications of this observation need to be carefully evaluated in future clinical trials of all serotypes of adenovirus-vectored vaccines.
The joint United Nations Program on HIV/AIDS (UNAIDS) estimates that more than 33 million people were living with HIV at the end of 2009 (1). As witnessed by a series of watershed results in the HIV prevention field of late, some progress has been made toward tackling this pandemic. Adult male circumcision (2–4), antiretroviral-based vaginal microbicides (5), preexposure prophylaxis (6), and antiretroviral therapy as a means of prevention (7) have shown varying degrees of efficacy, from modest to potent. These results have together energized the HIV prevention field and have provided a growing number of tools that could be brought to bear in global HIV disease control. However, as all of these approaches pose significant challenges for deployment as public health tools, a preventive HIV vaccine, development of which has thus far been elusive despite intensive research efforts, remains a critical goal (8).
There are three main types of vaccine being developed for the prevention of HIV infection: subunit vaccines, recombinant virus–vectored vaccines, and DNA vaccines. Three of the most significant clinical trials conducted thus far tested the efficacy of different combinations of the first two types of vaccine (9–11). When the first vaccine type was tested in two phase III clinical trials, it was disappointingly found that vaccination with repeated doses of gp120 protein subunit vaccines (AIDSVAX B/Bι and B/E) failed to protect either men who have sex with men (MSM) (10) or injection drug users (11) from HIV infection. Further disappointment came in the form of the results of the phase III Step study (9), which showed that three injections of a Merck-developed adenovirus serotype 5 (Ad5) vector containing gag/pol/nef HIV-1 gene inserts (referred to as the MRKAd5/HIV-1 vaccine) also failed to protect MSM. In contrast to these results, the RV144 trial demonstrated that an HIV vaccine might be possible (12). The approach tested in this trial was to first prime participants with four injections of a canarypox vector containing gag/pro/gp120/gp41 HIV-1 gene inserts (ALVAC-HIV) and then boost with two injections of a gp120 protein subunit vaccine (AIDSVAX-B/E), and it reduced the rate of HIV infection in a low-incidence population of Thais with heterosexual HIV transmission risk.
The Step study raised the added concern that, following vaccination, uncircumcised MSM with naturally acquired immunity to Ad5, in the guise of preexisting Ad5-specific neutralizing antibodies (nAbs), appeared to experience a transient period of increased risk of infection with HIV (13). These concerns led to the cancellation of a planned phase IIB clinical trial of a related Ad5-vectored gag/pol/env vaccine, which was to be used together with a DNA vaccine prime, in diverse risk groups and the generation of a new, smaller efficacy study focusing on circumcised MSM with no serologic evidence of previous Ad5 exposure (14). Additional research has suggested that the immunogenicity of the proteins encoded by the genes inserted into the Ad5 vector was reduced by preexisting Ad5-specific nAbs (15).
The failure of the MRKAd5/HIV-1 vaccine to provide protection from infection with HIV and the concerns it raised regarding preexisting Ad5-specific nAbs was a severe setback, but it did not eliminate all interest in using adenoviral vectors in candidate vaccines, as these platforms are highly attractive in terms of their marked immunogenicity, low cost, and production efficiency. However, the Step results did spur interest in the development of adenoviral vectors from both human and non-human primate adenoviruses with a lower global prevalence of preexisting nAbs — so-called rare serotype adenoviral vectors — as substitutes for Ad5. Rich debate continues on predicting the utility of these rare serotype adenoviral vectors based on type-specific nAb prevalence (16, 17).
In this issue of the JCI, Frahm et al. examine the impact of evoked cellular immune responses to Ad5 on subsequent immunogenicity to HIV-specific inserts expressed in human volunteers (18), which has been less studied than humoral responses. This is important because cellular immune epitopes may be more broadly shared among adenovirus serotypes than humoral epitopes. Using samples largely from the Step study, the authors asked whether measures of cellular immune reactivity to the Ad5 vector have implications for the immunogenicity of the insert-encoded HIV proteins. Vaccine-evoked adenovirus-specific CD4+ T cell responses were found to correlate indirectly with both the magnitude of the CD4+ T cell responses directed toward the insert-encoded HIV proteins and the breadth of CD8+ T cell responses to these antigens. Importantly, these associations were not influenced by preexisting Ad5-specific nAbs. As some of the adenoviral cellular epitopes were shown to be prevalent across disparate adenovirus types, the data generated by Frahm and colleagues raise concerns about the suitability of rare serotype adenoviruses (e.g., Ad26 and Ad35) for vaccine development in populations with prevalent Ad5-reactive CD4+ T cells.
Prime boost vaccination strategies using rare serotype human adenoviral vectors have shown much promise (19). Rare serotype adenoviral vectors are in various stages of vaccine development for malaria, tuberculosis, hepatitis, and filoviruses. However, could the cross-reacting adenovirus-specific T cell responses detected by Frahm and colleagues (18) limit the potency of vaccines based on rare serotype human adenoviruses? Would this indicate the intrinsic unfeasibility of developing rare serotype human adenovirus–vectored vaccines? Will we, rather, need to turn to other alternative vectors derived from non-human primates (20), or should adenoviral vector approaches remain an active sector of vaccine development?
These are critical questions to answer, as the field of HIV vaccine development is now at a crossroads. Do we pursue the promising pathway leading from the RV 144 clinical trial (12) and further develop poxvirus gp120 prime boost strategies in different risk populations and in different geographical populations exposed to distinct circulating HIV subtypes? While the advantages of building on success are clear, there are obstacles to this pathway. Notably, as the gp120 products used in the poxvirus prime and the protein subunit boost are inherently specific to a defined HIV-1 subtype (subtype CRF01_AE in the poxvirus prime and CRF01_AE and B for the protein boost), they represent a challenge for the development of a globally effective vaccine. Alternatively, do we explore newer classes of HIV vaccine candidates with more universal subtype application using mosaic HIV gene designs (21) or related technologies?
The likely answer is suggested by the adage “When you come to a fork in the road, take it” (Figure 1). A product development focus would follow up RV144 by testing related products in vaccine efficacy studies in new risk groups, such as MSM in Thailand exposed to HIV subtype CRF01_AE and men and women in southern Africa exposed to subtype C. The other pathway stemming from the fork would explore global strategies using novel vector and insert combinations that could possibly work for all HIV-1 subtypes. The use of heterologous rare serotype human adenoviral vectors would fall into this category of research exploration (14). The promise of a globally effective vaccine derived from this research is highly attractive. The study of correlates of risk of infection and, ultimately, correlates of protection afforded by vaccines of this type is likely to be highly informative for understanding immunopathogenesis, immunogenetics, and viral biology given the diversity of populations and vaccine types tested in this framework.
A framework for HIV vaccine development. Two parallel pathways in an HIV vaccine development framework can be envisaged. One pathway (which leads to a regional vaccine strategy) builds on the poxvirus prime protein–subunit boost vaccine concept tested in the RV144 clinical trial (12). Such vaccines would test the ability of additional boosts and adjuvant formulations to improve the durability of protection observed in RV144 and evaluate performance in new risk and geographic populations. The second pathway (which would lead to a global vaccine strategy) seeks to evaluate universal or globally effective HIV vaccines using novel HIV vaccine types (including rare serotype human adenoviral vectors), insert design, adjuvants, and clinical study designs.
The impressive volume of cellular immunology data generated through the well executed studies of Frahm and colleagues (18) provide further evidence of the value of human immunology for the development of vaccines against HIV and other infectious pathogens. Will preexisting cellular immunity to Ad5 have a mitigating impact on the immunogenicity of HIV antigens vectored in rare serotype human adenoviral vectors? Frahm et al. did not have samples from such clinical trials available to them to test this hypothesis. However, clinical trials employing these vectors have started, and more will follow soon, which will allow for the hypothesis to be tested in the context of rigorous clinical investigation, thus providing critical insight to guide the development of a globally effective HIV vaccine.
The views expressed here belong solely to the author and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.
Conflict of interest: The author has declared that no conflict of interest exists.
Reference information: J Clin Invest. 2012;122(1):25–27. doi:10.1172/JCI60988
See the related article beginning on page 359.