Epidemiological considerations in planning HIV preventive vaccine trials

Introduction There is growing consensus that a safe, effective and accessible HIV vaccine offers the best long-term hope to control the AIDS epidemic, especially in developing countries, where more than 95% of all new HIV infections are occurring [1,2]. Much has been learned since 1987, when the first human trial of an HIV candidate vaccine was launched in the United States. The first generation of candidate vaccines was aimed mainly at inducing neutralizing antibodies using monomeric envelope glycoproteins derived from laboratory-adapted strains of HIV-1 (X4 strains, those using CXCR4 as second receptor). Today, a whole range of new candidate vaccines is being developed, with the goal of inducing broadly reactive neutralizing antibodies against clinical isolates of HIV-1 (R5 strains, those using CCR5 as second receptor), as well as cell-mediated immune responses [3]. Many of those candidate vaccines have been tested, or are undergoing testing, in primate models. Although animal experiments are instructive, human trials remain in the critical path to develop HIV vaccines, and the expectation is that several new candidate vaccines should soon move to trials in human volunteers. In the absence of definitive information regarding potential immune correlates of protection, several products, based on different vaccine concepts, would have to be tested simultaneously in phase I/II trials, to evaluate their safety and immunogenicity in human volunteers. The best candidate vaccines will then be selected for phase III efficacy evaluation in large-scale field trials. Several trials will be needed to assess the efficacy of different vaccine concepts, against different virus subtypes, and in different populations (which may differ in route of transmission of the virus, and genetic, nutritional or health characteristics). To address these multiple questions, a number of phase III trials will have to be conducted in both industrialized and developing countries, and this will require intense international cooperation and collaboration. Identification and strengthening of potential sites for trials The effort to identify and strengthen potential sites for HIV vaccine efficacy trials started in the United States and in other industrialized and developing countries during the early 1990s [4]. Before field trials of HIV vaccines could be conducted, several critical issues had to be addressed, such as strengthening the research infrastructure for clinical trials, monitoring HIV variability, and ethical and social-behavioural matters [5]. The conduct of large-scale trials requires strong political and community commitment and support. Scientists, community members, and national authorities from developing countries should be involved as full partners in the planning and conduct of vaccine trial preparations. This serves two functions: first, to avoid foreseeable logistics and technical problems; and second, to begin to build a relationship of trust that will be essential for the successful completion of difficulty and lengthy efficacy trials. Vaccine trial preparedness efforts implemented during the 1990s included the development of prospective cohorts of HIV-negative volunteers at high risk of HIV infection that could be enrolled into efficacy trials. Unfortunately, only one candidate vaccine entered phase III clinical trials in the United States and Thailand, in 1998 and 1999, respectively [6]. As a result, few of those well-characterized cohorts were ever used to conduct phase III trials, although they have provided important information that would facilitate the implementation of future trials. The establishment of prospective cohorts is an expensive and time-consuming exercise, and most of the recently published data, which will be reviewed in this paper, come from studies that were initiated several years ago. Transitioning from phase I to phase III trials The clinical and epidemiological requirements for phase I, II and III trials are different, but they should be considered as sequential steps of a continuous process. Phase I trials provide initial safety and immunogenicity data, and are usually conducted among small numbers of volunteers (30-50) at relatively low risk of HIV infection. Phase II trials provide additional safety and immunogenicity information in different populations, and are usually conducted among a larger number of volunteers (in the hundreds) including people at higher risk of HIV infection representing the population in which the phase III trial would be implemented. Phase III trials are designed as large-scale, double-blinded controlled trials, involving thousands of volunteers (depending on HIV incidence), and conducted to assess the efficacy of the candidate vaccine in preventing HIV infection or disease. Traditionally, phase I trials are conducted in the country of origin of the candidate vaccine, usually an industrialized country. This approach has been justified by several scientific, ethical and political reasons. From the scientific point of view, it is essential that the first introduction of a candidate vaccine in humans is properly monitored, especially in relation to potential side effects, and some developing countries may not have the necessary scientific infrastructure readily available. In addition, some developing countries may lack appropriate regulatory mechanisms to identify candidate vaccines that are ready for testing in human trials. Having said this, it is important to emphasize that there are no formal ethical impediments for the conduct of phase I trials in developing countries, provided such trials are carried out for valid scientific and public health reasons, and provided the host country can ensure sufficient scientific standards and ethical safeguards [7]. One satisfactory approach could be to begin trials simultaneously in both the country where the candidate vaccine was produced and in the developing country where phase III trials are planned. The conduct of phase I/II trials requires considerable clinical and laboratory expertise. On the laboratory side, it is critical to use state-of-the-art technology to assess humoral and/or cellular immune responses to the candidate vaccine. Likewise, it is essential that vaccine evaluation centres have access to the appropriate methodology to study virologic and immunological aspects related to intercurrent (breakthrough) HIV infections, including measurement of virus loads and the genetic, biological and immunological characterization of intercurrent strains. The complexity of these techniques, which are constantly evolving, requires a cooperative approach, in collaboration with selected reference laboratories. The conduct of phase I/II trials not only provides critical information needed to make decisions about moving to phase III trials, but also offers an opportunity for training and capacity building in preparation for the larger and more complex phase III trials. In addition, phase I/II trials offer an opportunity for communities to become acquainted with and to build consensus around HIV vaccine activities in the country, and to develop mechanisms for the scientific and ethical review and monitoring of vaccine-related research. The first HIV vaccine trial in a developing country was initiated in 1993 in China. Since then, 11 phase I/II trials have been conducted or initiated in developing countries, with seven trials conducted in Thailand, and one in each of Brazil, China, Cuba and Uganda [1]. Results from phase I/II trials in developing countries were recently reported from Thailand, Cuba and Uganda. Two different groups in Thailand [8,9] tested gp120 candidate vaccines, with safety and immunogenicity results comparable with those obtained from trials in the United States [10]. Although these initial Thai trials used candidate vaccines based on subtype B strains (MN and SF-2), they provided a basis for the development of similar antigens based on subtype E, which is the HIV genetic variant prevalent in Thailand [11-14]. Investigators from Cuba also reported initial results of a phase I trial using a multi-antigenic synthetic peptide bearing several V3 sequences (TAB9) [15,16]. Initial results from the first HIV vaccine trial in Africa were reported at the XIII International Conference on AIDS, Durban, South Africa [17], using a subtype B canarypox-HIV recombinant candidate vaccine (ALVAC vCP205). Because most infections in Uganda are caused by subtype A and D strains [18], the choice of a subtype B vaccine was based on an anticipated cross-recognition of conserved cytotoxic T lymphocyte epitopes between different HIV subtypes [19,20]. Although a relatively low frequency of HIV-specific cytotoxic T lymphocyte responses was documented in vaccinated volunteers, the trial successfully demonstrated the feasibility of conducting scientifically valid vaccine research in Uganda. Several new phase I/II trials are expected to begin in industrialized and developing countries in 2001. A multicentric phase II trial has been approved for implementation in several countries in Latin America and the Caribbean (Brazil, Haiti, and Trinidad & Tobago) to assess the safety and immunogenicity of a subtype B prime-boost regimen (canarypox-HIV followed by gp120), in anticipation of a phase III trial planned to be conducted in those countries and in the United States. The next phase I/II trial in Africa is planned in Kenya, using DNA immunization and a Modified Vaccinia Ankara vector expressing subtype A antigens [21]. The conduct of phase III trials presents some difficult challenges, recently reviewed by Excler and Beyer [22]. In addition to the necessary political and community support, the host country must satisfy a number of epidemiological requirements (to be reviewed in the following two sections). It should also have in place the necessary mechanisms to guarantee an appropriate review and approval process (regulatory, scientific and ethical). And it should have the clinical, laboratory and epidemiological infrastructures to handle thousands of volunteers participating in a trial. Identification of populations with high HIV incidence for phase III trials To obtain statistically significant information on potential protective efficacy of HIV candidate vaccines, phase III trials should be conducted in well-defined populations with relatively high HIV incidence. The calculation of sample size depends primarily on the incidence of the primary end-point that is used to measure vaccine efficacy, the duration of study follow-up, the rate of retention of trial participants, and the minimum level of efficacy that the trial is powered to detect. For example, assuming a 1-year recruitment period, 3 years of follow-up, 5% of volunteers lost to follow-up per year, and a 1% annual HIV incidence, 2500 participants would be required for a placebo-controlled, two-arm trial powered to detect a minimum 60% efficacy with a 30% lower 95% confidence bound [23]. Potential populations suitable for HIV vaccine efficacy trials can be identified from cohorts of HIV-negative volunteers at higher risk of HIV infection [24]. Accurate estimates of HIV incidence can then be prospectively estimated, taking into consideration the effect of nonvaccine interventions (education, counselling, condom promotion, and, possibly, treatment of sexually transmitted diseases). In addition, cohorts provide essential information on the ability to recruit and retain volunteers over the several years that a phase III trial will last. Cohort studies also provide important information on variation of the HIV incidence rates due to intense counselling and education. HIV incidence may vary over time in a closed cohort, due to a saturation effect, or by the simple fact of participating in the study ('cohort effect'). A new proposed approach to estimate HIV incidence is utilizing the combination of two serological tests with different to with lower of antibodies may a for of populations with high of to be and especially in populations with B studies of HIV have also been conducted in an to identify populations that could be enrolled in phase III trials of HIV vaccines, that high HIV is by high HIV incidence. two of studies and the of not other important information for phase III trials, such as of the or the ability to recruit and retain volunteers. In the several developing countries Brazil, Thailand and in the development of AIDS Vaccine which included the establishment of cohorts for HIV vaccine trials The of of the United States has also development in several cohorts of and were in (in and In addition to community and support, these cohorts have also provided essential epidemiological information for the future conduct of phase III trials in The in which enrolled volunteers from to 1999, an annual HIV incidence of of in had an annual HIV incidence of and a follow-up rate of populations have been in Thailand as potential populations for phase III trials. A prospective of in in an HIV incidence rate of HIV incidence has high in this cohort, which is the one from which volunteers were for the phase III trial that started in in that country [6]. sexually transmitted in Thailand were also as a potential population for HIV vaccine trials, although incidence was lower than expected that vaccine trials in this population would have to be larger than In of the HIV incidence in populations, studies are being considered in Thailand the of conducting vaccine trials in identified populations is relatively to vaccine efficacy studies have been conducted in trials. and A HIV and incidence have been recently published from several countries, and the results the different of the epidemic, with in countries with as Uganda and and rates in countries with more as South A prospective of in documented a in the risk of HIV infection during in the with most occurring during the first of the In this HIV incidence during the 3 years of follow-up, from to The that to in HIV incidence populations could in vaccine trials with an number of to A study conducted among an in the of Uganda also that HIV has from in 1993 to in A of in which had a HIV at the time of demonstrated a annual incidence of with the that this could be a potential population for HIV vaccine evaluation proposed potential population for HIV vaccine trials is in the health in South Africa In this the annual HIV incidence from in to in HIV among in was high although this may not be an appropriate population for HIV vaccine trials due to the to ensure appropriate follow-up of The studies the of appropriate populations for HIV vaccine trials, which in fact may no be appropriate by the time the candidate vaccine is ready for or when the trial is approved by the national Although the initial HIV vaccine trials in developing countries were approved only of evaluation and with the over the few the approval process has been considerable HIV genetic subtypes and planning of efficacy trials The potential of the genetic of HIV in of is not has that HIV-1 genetic subtypes not to than one genetic subtype could protective and it is also that more than one is a genetic subtype [1]. The of may also on of immune is for In neutralizing antibodies to be more cell-mediated immune responses are more regarding the of different HIV genetic subtypes, and their immunological is important to the of new candidate vaccines and to clinical trials, especially phase III trials. To for it would be important that initial phase III trials are conducted with candidate vaccines that strains prevalent in the trial at some point in the it would be necessary to out additional efficacy trials to the of between different subtypes [1]. to the of would to two candidate vaccines produced to to two different HIV and these in a trial against or to conduct the trial in a population where two HIV are and the study to efficacy against A significant effort has been by different national and international HIV vaccine to obtain information on the of the different genetic subtypes of HIV-1 As a result, have a of the and of HIV-1 subtypes around the including that of the recombinant The prevalent virus in the and subtype which is the subtype on which most candidate vaccines are This may in the with new subtypes being in different of the For in addition to subtype subtype are also in several South countries, and subtype is the most prevalent subtype in In addition to subtypes B and a recombinant is in epidemiological of the that the frequency of infection with subtype was higher among with in which subtype B is prevalent A complex is in In one study from potential HIV vaccine evaluation sites in that country, the of strains were subtype B followed by subtypes and In this of subtype B with different at the of the V3 were with a of which is a in from the United States. Although the immunological of the V3 is not it was that different strains may differ in the rate of to AIDS, which should be into in the of candidate vaccines and vaccine trials in In addition, it was reported that of infections in were caused by recombinant The in Thailand has been well with subtype the and subtype B being with the among but being by subtype potential for the of candidate vaccines for testing in Thailand is the that the genetic of the envelope among subtype strains is growing with from in to in representing the of the The in Africa is with multiple subtypes, with subtype being the most prevalent in Africa and subtypes A and D in Africa and an recombinant being most prevalent in Africa Although subtypes A and D the prevalent strains in the of subtype to be over A study from Uganda of subtypes A and D and with subtype identified in of the It is important to that although both subtypes A and D are in all of their is among different Two other countries, and also have caused by subtypes A and as well as by subtype Vaccine for Africa may have to be to address the incidence of subtype infections, in addition to the subtype A and D of HIV strains from different countries in and Africa that of the had subtypes between and with subtypes A and involved in the by the as recombinant As move to the more of from a to be followed by subtypes and A conducted in the of that all HIV subtypes and that of the could not be A was the one and with subtypes and from to and subtypes and strains representing of the one subtype B was of had subtype between and The of different genetic subtypes of HIV in different of the which will in the presents both a and an The is to identify sites where the candidate vaccine can be properly to the The opportunity is based on the to and to the fact that a future HIV vaccine will have to against all genetic subtypes of designed efficacy trials, sites with multiple subtypes may to obtain information on the of of different HIV candidate vaccines and vaccine and retention of volunteers As and other studies are necessary to assess the feasibility of and volunteers, as well as to their to in vaccine trials. In addition, these studies offer the opportunity of information on the effect on HIV incidence of interventions for ethical reasons, should be to all volunteers. has been in the United States the of the Vaccine For epidemiological reasons, and have been identified as a potential population for HIV vaccine trials in the United States. to obtain information on the efficacy of candidate vaccines against a effort is also been to recruit into trials in the United States In one the of to in HIV vaccine trials, although were to about vaccine concepts, and were more to be lost to follow-up most to in HIV vaccine trials was the to to the and to to was to with and this may require a continuous effort at community and This effort must into the of vaccine their for trial and of potential side Since phase III trials will require the of thousands of volunteers, for information on risk are being developed, including and issues have been among participants in a phase I/II trial in Thailand, where of the volunteers reported from or although no with in health or In preparation for a phase III trial in Thailand, to was among in with more than that they would in the and only not to it HIV and were to be important for has also been recently published from of the cohorts of HIV-negative and In the cohort, of participants reported that they would in HIV vaccine trials, with 30% that they of volunteers from the of in reported their to with being the of infection and serological tests were the for not to to this are the results obtained from of in that and of risk not into since significant of the In and regarding vaccines in and HIV vaccines in was among people participating in the in Although the community had of in that HIV vaccines were that HIV vaccines were being tested, and only that a vaccine would control The of conducting multiple HIV vaccine trials in industrialized and developing countries has an intense international on the ethical conduct of those trials To address some of those the United on on a process of international to important ethical and to that facilitate the ethical and conduct of those trials As a result, in a on in HIV vaccine [7]. In the some of the critical that must be considered when planning and HIV vaccine trials. of the ethical of the international community to HIV vaccine based on between the different This to capacity building in the host countries, where of the trials will be conducted, and where future vaccines will be needed as a of The a strong to to ensure the ethical and scientific of the proposed and to and by the community is to such as in the implementation of and to the to facilitate an about scientific and issues related to HIV vaccine evaluation The also early planning to make a future vaccine to the community where trials are conducted, and to other populations in of the vaccine years of the first phase III trial of an HIV vaccine was initiated in the United States in 1998 using a gp120 candidate vaccine [6]. some initial regarding the difficulty of sufficient number of volunteers for HIV vaccine trials the trial successfully the required sample size of volunteers in sites in America and gp120 based on B and strains, also entered phase III trial in in a population of 2500 efficacy in the and trial will be conducted in and efficacy in In the Thai first efficacy will be conducted in and in In the it is essential to efforts to develop and evaluate new candidate vaccines which will require the preparation of multiple vaccine evaluation sites in industrialized and developing are being by the the of the for and the International AIDS Vaccine the for on AIDS, the and the HIV Vaccine among of these new the recently the of international sites for their HIV Vaccine in Brazil, China, Haiti, South Thailand and the International AIDS Vaccine is developing a number of to the development of HIV vaccines appropriate for developing and the HIV Vaccine is in the development of a AIDS Vaccine In to this vaccine preparedness it is also important to the of candidate vaccines for testing in human volunteers, including based on different HIV a number of HIV candidate vaccines should be tested in phase I/II trials, to the of the best for phase III the a approach was to cohorts for future HIV vaccine efficacy trials. As few of those cohorts were enrolled in trials of the lack of appropriate candidate vaccines for testing the lack of to also learned that HIV incidence may to with time in those due to the intense effort that is provided during the although not for that lower HIV incidence can be should be including the and recruitment of populations with in which HIV incidence to be higher than in populations with populations may be in and they could be identified with the of new laboratory such as the approach that additional consideration is the conduct of trials, several thousands of volunteers with lower HIV incidence This approach, would require a higher level of than that which has been not only to and the appropriate study populations, but also to the required larger number of of the candidate vaccine. vaccine efficacy is demonstrated in a phase III it would be HIV vaccines will be protective against infections by different some point in the development efficacy should be in different appropriate consideration should also be to the epidemiological for the conduct of future trials that may be required initial efficacy of HIV candidate vaccines is demonstrated in phase III trials. trials may to of thousands of participants, and they be necessary to provide information needed to develop appropriate for public health use of future safe, effective and HIV The and for