Well into the third decade of the struggle to understand, prevent, and treat HIV infection and AIDS, AIDS vaccine research and development must be viewed in the context of the overall effort. Since HIV-1 was identified, a vaccine has been an important goal. The early decades of this search were full of disappointment, but in the past year significant new information gives hope that this goal is achievable. In this paper, we briefly review the overall state of the field and the importance of African research to the eventual success of this endeavor.
Scientific challenges to the development of an AIDS vaccine
The scientific challenges for development of a preventive HIV vaccine are many and have been well described . Development of an AIDS vaccine is one of the most difficult challenges faced by medical scientists. There is no clear evidence of a single protective mechanism; humans do not recover from HIV infection and individuals infected with HIV-1 can be super-infected by a new strain of HIV-1 from the same or a different subtype. The best animal model for studies of pathogenesis or control by cell-mediated immunity is the macaque infection by SIV, but challenge strains of SIV are very insensitive to neutralization by antibodies, hence for studies of neutralizing antibody protection, the simian human immunodeficiency virus (SHIV) chimeras, with the HIV envelope, are generally employed. These viruses can be neutralized, but how closely this model corresponds to HIV infection is unknown. Nevertheless, studies in animal models support the notion that a vaccine should induce both a neutralizing antibody response to block infection and cell-mediated immunity to limit replication if infection is established. Epidemiological studies support this concept as well; HLA-restricted cell-mediated immune responses develop soon after infection and seem to be correlated with control of HIV replication, based on lower or higher virus load (quantity of virus in plasma). Antibody protection may be responsible for the fact that many infants do not become infected with HIV despite extensive exposure during birth and breastfeeding. Additional factors of importance, including genetic associations with resistance to HIV infection, will not be reviewed here, as they are not inducible by vaccine. However, they may provide challenges to design of vaccines and interpretation of vaccine trials, as well as opportunities for further understanding and perhaps intervention of HIV infection and AIDS [2,3].
Another great challenge to development of a prophylactic HIV vaccine is the extensive variation of HIV; the virus mutates within each person and mutants soon arise that are able to evade cell-mediated and humoral immunity. This poses severe difficulties in designing vaccines to induce broadly effective humoral and cell-mediated immunity, as discussed below.
To prevent infection, neutralizing antibodies must be potent enough to completely and irreversibly neutralize HIV when a person is first exposed, because virus escape from antibodies made after infection is common [4,5]. Neutralizing antibodies against the predominant HIV in the patient are initially not broad in their specificity and broadly neutralizing antibodies remain relatively rare, even in people with chronic HIV infection. Because of the vast and increasing variability of HIV, very broadly neutralizing antibodies will be needed for protection against infection [6–10]. Currently, there is no known method to induce production of such antibodies with vaccination.
Several broadly neutralizing antibodies have been isolated from the B cells of HIV positive individuals [6,11–14]. Structural studies are beginning to define the shapes of these antibodies and the sequences are known. However, the key to instructing the immune system to make such antibodies remains elusive.
Two monoclonal antibodies from an African donor have been cloned and characterized; these are more potent than previously identified monoclonal antibodies, neutralize a broad spectrum of African and Asian viruses and bind to a target on the HIV envelope that has not been characterized previously . A global consortium of clinical investigators, supported by IAVI screened over 1800 persons who had been infected with HIV for at least 3 years and remained in good health. Plasma samples were screened against a panel of viruses, and the donors of broadly neutralizing antibodies (bnAbs) were selected for harvest of PBMC and attempted cloning of the antibodies . Additional antibodies with similar breadth and potency are now being identified by other groups using different methods [12,13,17].
Coupled with the recent demonstration in macaques that a relatively low dose of antibody can protect against a chimeric SHIV , the isolation of the new antibodies provides hope that the goal of creating a vaccine that will induce sufficient neutralizing antibodies to protect against infection is possible. Currently, the IAVI-supported Neutralizing Antibody Consortium (NAC) and other groups are attempting to determine the detailed structure of bnAbs and to engineer an immunogen that will fit tightly with these antibodies in the hope that it would also induce the antibodies [16,19]. An alternative approach, though somewhat unconventional, is to incorporate the gene coding for an antibody-derived immunoadhesin into a viral vector. In nonhuman primate (NHP) trials, some macaques were protected against infection with SIV by gene transfer . Such an approach could be used to protect humans, if long-term expression of antibodies or antibody-like genes can be induced without undue risks.
A complementary method for protection against HIV is the induction of cell-mediated immunity (CMI). T-cells limit viral production by destroying HIV-infected cells or by releasing chemokines that slow virus production. Evidence for the effectiveness of CMI is found both in studies of human HIV infection and in NHPs. During acute infection, HIV virus load increases rapidly. However, most HIV-infected individuals can partially control viral replication and virus load often remains low for many years. Cytotoxic or virus-inhibiting T cells have been shown to mediate at least some of this effect [6,21,22]. Likewise, a number of vaccines that induce CMI against SIV have been able to mitigate infection after subsequent challenge, reduce the quantity of SIV found in the blood (viral load) during the peak of acute infection, lower the later ‘set-point’, and delay the onset of disease [23,24]. Notably, vaccination with recombinant, replication-competent Rhesus cytomegalovirus containing gag, env, rev, tat, and nef genes of SIV has conferred an extraordinary degree of control over SIV in about half the vaccinated macaques; SIV was never or only transiently detectable in these animals, which remained healthy for over a year following infection .
AIDS vaccine clinical trials, phase 1 and 2
Since 1987, AIDS Vaccine clinical trials have been conducted throughout the world, testing vaccine candidates made of protein or peptide subunits, DNA plasmids, and recombinant viral or bacterial vectors that are generally unable to replicate [25,26]. As of the end of 2009, nearly 200 trials, employing a variety of vaccine types alone or in combination, were recorded in the IAVI Clinical Trials Database (www.iavi.org) (Table 1). Additional information about many recent trials can be found in the United States Public Health Service database at www.clinicaltrials.gov and other registries. There have been very few safety problems in preventive AIDS vaccine trials. The majority of the products tested are no longer in clinical development because they failed to meet immunogenicity endpoints. As a result of concerns about limited immunogenicity, a number of trials have been conducted using two different vaccines in sequence or in combination (so-called prime-boost strategy), including many trials combining a DNA plasmid with a viral vector, based on either poxvirus or adenovirus, combining DNA plasmid with protein, or combining a protein vaccine with a viral vector. In general, the prime-boost trials have shown a synergistic or additive effect of the two components. RV144, the most recent efficacy trial in Thailand showed some reduced incidence of infection in the group that received a prime-boost vaccine regimen of the protein gp120 with the poxvirus vector ALVAC encoding multiple genes. An efficacy trial of a prime-boost regimen using DNA plasmid plus Adenovirus 5-based vaccine containing three envelope genes and gag, pol, and nef, is now underway in the United States.
Approximately, 21 preventive HIV vaccine trials have been conducted in Sub-Saharan Africa (Table 2). The first vaccine trial in Africa started in 1999 [27,28], using a recombinant attenuated canary pox vaccine encoding Env, Gag, and Protease. The vaccine was based on subtype B virus more common in the developed world, but it was expected that the Env portion of the vaccine would be changed to A, whereas leaving the clade B gag and pol components, because the internal components were considered to be adequately cross-reactive; therefore, the immunologic data from this trial would, in part, reflect reactions to the anticipated ‘Clade A’ vaccine. The vaccine elicited both clade-specific and cross-reactive T cells .
The lack of vaccine candidates based on subtypes common in the developing world was one of the reasons for the creation of IAVI in 1996, which partnered with the Medical Research Council of the UK (MRC) and the University of Nairobi to test the first vaccine based on a subtype A strain common in Africa [29,30]. Currently, a number of vaccine candidates include antigens based on HIV sequences from Africa, Thailand, India or China, including DNA and MVA vaccines designed and constructed in Africa .
Currently, there is considerable focus on nonreplicating vectors as a basis for HIV vaccines, often in combination with either a DNA plasmid or a protein, an approach called (heterologous) ‘prime-boost’ [13,32]. DNA plasmids appear to be more immunogenic in humans when delivered by electroporation. In addition, combinations of vaccines based on different vectors, such as Adenovirus serotypes 26 and 35 with each other or with a poxvirus, are under consideration. Recent preclinical studies are focusing more on replicating vectors [33,34] and clinical trials of newer replicating vectors will begin soon. However, it should be recalled that a replication-competent recombinant vaccinia virus was one of the first preventive HIV vaccine candidates .
Human efficacy trials: considerations relating to populations
Two efficacy trials have enrolled participants in the United States (and elsewhere) and a third the United States-based trial is now underway (Table 3). In the Americas, these trials have enrolled both at-risk men who have sex with men (MSM) and women at risk because of multiple partners or partners engaged in injection drug use. The results of the VaxGen and STEP trials show that populations of at-risk MSM can be recruited to such trials, but women enrolled had a lower risk; the women who enrolled may have engaged in unprotected sex, as evidenced by pregnancies and sexually transmitted infections, but did not have a high risk for HIV infection . Hence, unless newer strategies are found, the search for a vaccine to protect the general population, including women, must enroll populations from regions other than North America. The one efficacy trial that began in South Africa enrolled both men and women at risk successfully until it was halted (www.phambili.org.za).
In Thailand, the first efficacy trial, VaxGen 003, was implemented in a cohort of injection drug users (IDU). Continued use of such cohorts faces challenges both from changing drug abuse practices and from the growing consensus that there is an ethical imperative to provide clean injection equipment to an enrolled population, which should reduce incidence dramatically.
The Thai and the United States Military teams that carried out the recent RV144 trial and their industry partners broke new ground for HIV vaccine studies in enrolling a general population, thus requiring a sample size of about 16 000 persons. This approach may eventually be employed elsewhere, if the goal of the trial is to obtain proof that the risk/benefit ratio of the vaccine is appropriate for a general population. An advantage is that enrolling a general population avoids attaching stigma to those enrolled and, indirectly, to the vaccine. It is important to consider whether a ‘low-incidence’ population is just a small number of persons at high risk plus a large excess of persons who are not at risk, or whether the risk for each person differs in a fundamental way. One obvious difference is that in a high prevalence population, each person at risk may be exposed to a number of different HIV strains; this might defeat a vaccine that protected against a relatively narrow spectrum of viruses, as most people with two or three sources of exposure would then be infected by a virus not covered by the vaccine-induced immunity. On the contrary, the average number of viruses to which each person is exposed would be of less importance if the vaccine induces broad immunity. Two approaches to making immunogens that induce broad immunity are the computer-designed mosaic antigens ) and antigens based on the conserved portions of the HIV genome [38,39].
In Africa, some general population or occupational cohorts have significant risk , but extensive studies of cohorts of at-risk individuals have defined two basic populations at high risk of HIV infection who might participate in future efficacy trials. One population is persons with multiple partners, including sex workers [41–46] and MSM in which incidence ranges as high as 8–10 per 100 person years [47,48]. The other is married or cohabiting couples in which one partner is HIV positive and one is HIV negative, who are at high risk even after counseling and condom provision, a type of cohort that has contributed enormously to our understanding of heterosexual transmission as well as the course of HIV infection, with incidence in the range of 2–7 per 100 person years and very high rates of follow-up [49–51].
As education, circumcision, more widespread and effective antiretroviral treatment and perhaps, in years to come, antiretroviral-based prevention technologies such as preexposure and postexposure prophylaxis and/or microbicides, spread throughout Africa, it is to be hoped that incidence of new HIV infections will fall. This will necessitate new strategies or larger efficacy trials, if vaccines are to be proven effective.
Human efficacy trials: results to date and next steps
Four AIDS vaccine efficacy trials have been completed, one was halted and one is underway (Table 3). The first three showed no overall benefit [52–54] and the Phambili trial in South Africa was stopped before completion because the adenovirus type 5 (Ad5) vector-based HIV vaccine it employed had proven not to be protective in the STEP trial.
In the STEP trial, there was an early, transient trend toward more infections in the vaccine arm that appeared to be associated with preexisting immunity to the vector, adenovirus type 5 and/or lack of circumcision in this population of MSM. Analysis of immune responses in the STEP trial suggest that an immune response with some impact on HIV replication was mounted by some vaccines, but that it lacked potency and/or breadth . Additional analysis is ongoing to define the extent of antiviral effect by the vaccine. The next step for this research is the ongoing HVTN 505 trial, in which a DNA plasmid prime and Ad5 vaccine boost is being used; these vaccines contain envelope as well as Gag, Pol and (in the DNA vaccine) Nef. This trial enrolls MSM who are circumcized and lack prior immunity to Ad5, in order to minimize the risk of increased HIV acquisition. An alternative approach, using adenoviruses that are rare human serotypes, and in some cases use different receptors, such as Ad26 and Ad35, or adenoviruses isolated from nonhuman primates, is being pursued by a number of groups, to avoid any detrimental effects of prior immunity to the vector.
In another trial, the vaccine regimen of four doses of ALVAC-HIV and two doses of gp120 (recombinant envelope protein) were tested in a general population in Thailand; these vaccines were based on the circulating recombinant strain found in Thailand and on Clade B, which is also found there. The trial enrolled more than 16 000 persons from the general population. The vaccine regimen showed an efficacy of 31% over 3 years (P = 0.04) according to the analysis that included 16 395 volunteers (the modified intention to treat analysis, with all volunteers included except seven who were in the very early phase of HIV infection at enrolment) . Another analysis, the perprotocol analysis, which excluded volunteers with missed or late vaccinations and all infections that occurred in the 6 months prior to the end of vaccination, included only 12 452 volunteers, and fell short of statistical significance. However, the trends were similar . Most of the protection appeared to be in the first year after vaccination. The result is not statistically robust, so some type of repeated trial will be needed. Discussions are ongoing regarding further studies both in Thailand and in Africa, but it seems likely that an efficacy trial combining a regimen constructed from an envelope protein, a poxvirus vector, and possibly a DNA plasmid will be carried forward, in an attempt to improve on the ALVAC along with gp120 regimen tested in Thailand. Additional work to better define the immune responses and look for selection of HIV strains by the vaccine is ongoing.
The Thai trial has many lessons to teach and raises additional questions. The role of the two individual vaccines and the mechanism of protection remain unknown. The immune responses usually measured in vaccine trials were not impressive, leading to early pessimism about the prospects for success . Detailed studies of the infecting viruses and immune responses are ongoing. Unlike other efficacy trials, this one was conducted in a general population, not a specific high-risk population, but it is unknown whether individual activities and exposures of those who acquired HIV infection differ greatly from the exposures in some ‘at-risk’ cohorts, particularly the discordant couple cohorts that are found in Africa [51,58,59].
The failure of the Ad5 vaccine to provide significant protection led to a more in-depth analysis of the breadth of the immune responses induced by this and other vaccines in development (i.e. the number of epitopes to which the average vaccinated person responds). If these epitopes are present in a highly variable region of the virus, they may be ineffective, as many viruses will lack them, or will be able to escape via mutation. Two approaches are under way to improve the components of vaccines designed to induce T cell responses: one is to create HIV genes optimized through computer analysis to contain epitopes matching the maximum number of viruses, the mosaic inserts , whereas the other is to remove the presumably less relevant variable regions to focus the response on conserved portions of HIV that it cannot change without a high fitness cost [38,39]. These inserts will soon be incorporated into vectors or DNA plasmids for human trials.
In addition to T cell antigens, intense effort is going into the creation of immunogens to induce broadly cross-reactive antibodies, with little success to date. In addition, other functions of antibody are being investigated .
The role of international partnerships in AIDS vaccine research and development
In 1991, WHO identified four countries – Brazil, Rwanda, Thailand, and Uganda as future sites for vaccine trials . National AIDS Vaccine Plans were developed in these countries in 1992–1993 in close collaboration with national authorities and scientists. The WHO virus isolation and characterization network, which included primary laboratories in these four countries and a number of secondary laboratories in the developed world, collected viruses, sera, and cells and made them freely and widely available . These specimens continue to contribute to vaccine research and development via the United States National Institutes of Health (www.aidsreagent.org) and UK Medical Research Council (www.nibsc.ac.uk/catalog/aids-reagent/) repositories. Molecular epidemiology studies in Africa, from early on, identified multiple subtypes including recombinant viruses [62,63].
Preparation for efficacy trials requires significant building of skills including Good Clinical Practices, Good Clinical Laboratory Practices, data management, specific laboratory techniques, a detailed understanding of the risk structure in the population to be studied and building of trust, cooperation and support within the community. In many settings it also requires infrastructure including clinical and laboratory buildings, standardized laboratory equipment, document storage, cold chain, pharmacy facilities, and communications–information technology. In developed countries, networks such as the HIV Vaccine Trials Network (HVTN) and other governmental support have added the specialized skills needed to an already adequate infrastructure and skills base. National governments in the United States and Europe have supported numerous Phase 1 and 2 HIV vaccine trials over the years. In Thailand, nearly two decades of work by the United States CDC and military in cooperation with the Thai government and others developed the capacity used for the HIV vaccine efficacy trials. Other governments including China, India, and Brazil are supporting capacity building and preparatory studies.
AIDS vaccine preparatory research and trials have been supported by many funding agencies from a variety of governments and international agencies, by private industry, and more recently by significant philanthropy (HIV Resource Tracking Report, AVAC, IAVI, UNAIDS, 2009, www.avac.org). Participation in HIV vaccine research has contributed to capacity development in many African institutions, largely through collaborations and funding from the North. African clinical research is supported by bilateral agreements with several European countries and Canada. The International AIDS Vaccine Initiative and the United States National Institutes of Health (NIH), in part through the HIV Vaccine Trials Network (HVTN), have provided significant support in preparation for such trials, including funds for cohort work, and Ph 1 and 2 trials (IAVI and NIH) and Ph 2B efficacy trials (HVTN). The United States Centers for Disease Control and Prevention (CDC), the United States Military HIV Research Program (USMHRP), UK Medical Research Council, Wellcome Trust, European and Developing Countries Clinical Trials Platform and other European bilateral partnerships with African governments and universities have fostered extraordinarily valuable clinical research groups. The South African AIDS Vaccine Initiative (SAAVI) set out a comprehensive agenda within South Africa to encompass preclinical, clinical, ethical and bioinformatics development . Increasingly, networks are being created among African clinical research centers. The African AIDS Vaccine Program plays an important role in coordination and support across all of Africa .
In difficult economic times, some research centers in Africa have been able to sustain their capacity and research programmes because of the multidisciplinary nature of their work. MRC/UVRI Uganda Research Unit is such an example, with a multidisciplinary approach to research that involves epidemiological studies of HIV, trials of various interventions designed to prevent HIV transmission, intervention studies to improve HIV/AIDS care, basic science studies and social science research relevant to HIV infection and other relevant diseases. This requires substantial, long-term investments to develop centers of excellence and, ideally, multiple funding sources. Working together with AIDS intervention programmes (other than vaccine research) and the AIDS care programmes, as well as bridging with research efforts in tuberculosis (TB), malaria, and other diseases can broaden the support base and increase the overall contribution of clinical research centers to public health.
Contribution of African research
Africa has borne the brunt of the HIV pandemic. Correspondingly, in all aspects of research on human HIV infection, African research groups, and cohorts of HIV-infected and uninfected individuals have made critically important contributions to the understanding and control of the epidemic in the context of Africa and globally. From early on, there have been population-based studies of behavioral, social, and biomedical intervention trials. African cohorts with high HIV prevalence and incidence coupled with diverse HIV-1 subtypes offer opportunities to investigate HIV transmission, the pathogenesis of HIV disease, and the role of possible protective immune responses. These cohorts have provided key information that has allowed us to understand the events around transmission, disease progression, possible protective host factors, and immune responses as well as on practical aspects of clinical care and preparation for HIV vaccine trials [41,58,66–114].
Importance of communication
An important need, in the complex environment of today, is for open communication and collaboration between different institutions, vaccine developers, and investigators who are conducting or wish to conduct vaccine trials, in particular efficacy trials. The Global HIV Vaccine Enterprise  serves an important role in sponsoring an annual congress and many less formal interchanges between the various groups, fostering a spirit of transparency, and collaboration. Clinical trials must be conducted in an open and fair environment. AIDS vaccine researchers are committed to a comprehensive approach that includes providing a broad array of effective prevention methods for those who are not infected and means for those who are HIV positive to protect those they love, treatment for those infected, and care for those who are ill. From a public health perspective, availability of voluntary counseling and testing, reduction of stigma, and a nondiscriminatory legal system are all important to support optimal prevention . It is essential to institute a continuous quality improvement system for research voluntary counseling and testing and to conduct periodic or ongoing assessment of healthcare referrals . Important guidance can be found in the WHO Good Participatory Practice guide for HIV prevention trials (http://data.unaids.org/pub/Manual/2007/jc1364_good_participatory_guidelines_en.pdf).
On the basis of epidemiology and animal model studies, a consensus has emerged that neutralizing antibody (present in advance of exposure in the target tissues) should help prevent infection and that CD8+CTL, particularly in target tissues such as mucosal exposed surfaces or gut-associated lymphoid tissue, should help limit virus replication. It may be possible for T cells and/or neutralizing antibody or other effectors to extinguish a local infection before virus replication and dissemination to the blood stream and peripheral targets. Several new findings raise considerable hope that an efficacious preventive vaccine can be developed, including the first protection by an AIDS vaccine, the isolation of potent and broad neutralizing monoclonal antibodies from humans, and the demonstration that several SIV vaccines provided significant protection against SIV replication in macaques and against simian AIDS.
Phase 1 and 2 HIV vaccine trials provide the data on the performance of a candidate vaccine; populations may differ significantly in many regards, including HLA-driven T cell responses, baseline immunity to a vaccine vectors, or differences in HIV risk and exposure. Efficacy trials, even if unexpected results are generated, provide valuable information for better design of trials and vaccine candidates. Prerequisites for and collateral benefits of trials include improved skills and infrastructure, as well as an increased level of knowledge about HIV prevention and treatment among the population from which volunteers are drawn, in the medical and scientific community, government, and the public.
Hence, a strong commitment to continued Phase 1 trials in relevant populations and vaccine efficacy or test of concept clinical trials with detailed analysis of the immune responses and breakthrough viruses, coupled with a judicious consideration of evolving evidence from epidemiology, animal models and basic science, is the ideal way forward.
We thank our colleagues for their dedication and the study participants for their invaluable support. In particular, we thank Arielle Ginsburg, Sabrina Welsh, and Lisa Gieber for maintaining and summarizing the IAVI Clinical Trials Database and Devika Zachariah for assistance with the manuscript.
This report is made possible by the generous support of the American people through the United States for International Development (USAID) and by the United Kingdom Medical Research Council. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government.
Conflicts of Interest: None.
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