The HIV vaccine pipeline, from preclinical to phase III

Introduction The AIDS epidemic continues to move inexorably around the globe, making its most recent inroads in China and Southeast Asia, and re-asserting itself in young gay men in places like New York City, after a period of successful behavior modification that had slowed the rate of new infections for a time. The United Nations acknowledges that HIV/AIDS could be a threat to world peace [1]. Worldwide, nearly 12 million men, women and children have become infected in just the past 2 years, and population life expectancy is actually going down in parts of sub-Saharan Africa. The developing world harbors 95% of these new infections, where there is little access to treatments that have prolonged life in industrialized countries. An effective and safe preventive vaccine remains the best hope for ending this pandemic. Vaccines have been cost-effective public health weapons against infectious disease, but some new road maps may be needed to achieve success against HIV. The favored tools of the past, live-attenuated strains and killed vaccines, have not provided a direct pathway to an AIDS vaccine. A truly attenuated and safe HIV that is still immunogenic has proven frustratingly elusive [2], and the difficulty in retaining the envelope glycoprotein on purified HIV particles has interfered with the manufacture of an adequate product to test the utility of the whole-killed approach. In addition, the challenge of producing millions of doses without allowing a single case of HIV from an improperly inactivated production lot, as would be required in the present climate, is daunting to say the least. Safely mimicking HIV infection as the modus operandi for the vaccine, using either the killed or the attenuated approach, has been frustrated so far by the biology and physical chemistry of HIV. Therefore, HIV vaccine design tilts heavily toward the 'modern' school, using the power of genetic engineering to take parts of HIV and create vaccines that could never cause AIDS. But will these 'modern' vaccines be immunogenic enough? While it is still not clear what facets of the immune response are most important for protection from infection or disease, it is now widely believed that an efficacious vaccine will need to induce both cellular and humoral immunity. This review will attempt to show the strengths and weaknesses of various approaches towards inducing and maintaining such immunity. Although each vaccine platform will have its special feature, let us not forget that all the candidates necessarily share one inescapable commonality - they must include the viral genes that contain the protective epitopes. Learning what antigens are protective, or what immune responses (or at which level of intensity or duration) are useful, can be obtained in one system, and that knowledge may be immediately transferable to the other approaches. Phase III timetable While increasingly valuable information is emerging from experiments in primates, an efficacy trial in humans under conditions of natural exposure to HIV is needed to truly prove the worth of a vaccine. In 1998, a large trial of recombinant gp120 (in a bivalent formulation combining a laboratory strain glycoprotein with a primary virus glycoprotein) began in the United States (also with sites in Canada and the Netherlands), mostly among gay men [3]. Another trial in Thailand, among intravenous drug users, completed enrollment in autumn 2000. Using gp120 to generate protective neutralizing antibody was among the earliest 'modern' vaccine concepts to emerge in the drive for an HIV vaccine [4,5], and it is now finally being put to the test. A first look at the protection data from the US trial will occur halfway through the trial in November 2001, according to the manufacturer (VaxGen, Brisbane, CA, USA). If the trial has a statistically valid lower bound of 30% efficacy at that time, the hypothesis that monomeric gp120 can prevent infection by a significant proportion of prevalent HIVs will have been proven. If the primary endpoint is not achieved in November 2001, the trial will proceed to completion. In that case, the utility of gp120 as a vaccine will have to wait until early 2003 for an answer. A second HIV vaccine is now in position for phase III clinical testing. In the years since work on gp120 began, a 'second generation' of HIV vaccines has developed, emphasizing cellular immune responses in addition to antibody and also investigating the role that proteins other than gp120 can play as protective antigens. Canarypox vaccines (ALVAC) of Aventis Pasteur (Lyon, France) are now in final phase II human trials after years of development work, devoted to learning the best way to express multiple antigens in a single recombinant vector and the most appropriate way to assess cellular immune responses. The National Institutes of Health HIV Vaccine Trials Network (HVTN) is testing a subtype B ALVAC that expresses the gag and pol genes as well as the env gene, plus epitopes from nef and int. The Walter Reed Army Institute of Research (WRAIR)/Henry M. Jackson Foundation has an ALVAC with gag and pol genes containing subtype E env in a phase II trial in Thailand. Each ALVAC vaccine probably would be tested in combination with a VaxGen gp120 boost, although none of the phase III trial protocols in development is final. If either the National Institutes of Health or WRAIR proceed with an efficacy test of the ALVAC/gp120, such a trial could begin in 2002 and not yield results until at least 2005. It is sobering to reflect on the time it takes to lead up to and then plan, mount, and enroll such trials, which then typically will run for 3 years after the last volunteer is enrolled, to assess the duration of any protective effect. This chapter will attempt to characterize what may come next for phase III clinical testing, but nothing that will be covered next is likely to be ready for phase III until 2004 or later. It will be a long wait. Envelope protein antigens (the neutralization conundrum) Monomeric gp120, the only candidate AIDS vaccine to advance to large-scale efficacy trials so far, was initially developed from laboratory strains of HIV and shown early on to be the most effective vaccine at inducing neutralizing antibodies against the laboratory strains available at the time. It was subsequently learned that HIV grown long-term in culture (i.e. a 'laboratory strain') was much more sensitive to neutralization than HIV freshly isolated from patients and only briefly adapted to culture (so-called 'primary strains') [6]. The antibodies induced in human volunteers by the original gp120 vaccines were incapable of neutralizing 'primary' HIV [7,8]. The consequences of this limited breadth of neutralization can be shown experimentally in a primate challenge study, where vaccination with a laboratory strain gp120 prevented infection if animals were challenged with a virus homologous to the vaccine but proved inadequate in protection against challenge with a heterologous virus based on a primary strain [9]. The current phase III trials of this vaccine approach will soon settle whether this research analysis is predictive of its protective potential in the real world. While it is beyond the scope of this review to address the details of HIV envelope structure and why getting vaccines to perform better in these laboratory analyses has been so hard [10], we digress to provide a short summary of attempts to improve envelope immunogens. One avenue for improvement is to design and produce immunogens that mimic 'native' HIV as closely as possible, on the assumption that the trimeric glycoprotein spike structure on the surface of primary HIV contains neutralization epitopes that cannot be duplicated on monomeric, recombinant gp120. Alternatively, on the assumption that primary HIV is intrinsically neutralization resistant because it has evolved mechanisms to hide neutralizing epitopes, another approach is to modify the structure of gp120 to expose those hidden and putatively effective neutralization epitopes. 'More native' envelope immunogens An early hypothesis to improve monomeric gp120 was to base the vaccine not on a laboratory strain, but on a primary strain. 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surface contains gp120 in of in this by with a of structure is not are after the is gp120 and and they are to be purified the envelope protein to prevent gp120 and but the of that that can be purified of neutralizing antibodies by these has been because these are not the In attempts to truly trimeric to the trimeric spike have been One has gp120 and but by the in a bound The of this are to the on the virus but the neutralizing antibodies induced in laboratory animals show little improvement those induced by gp120 Another has a envelope by and that both the and the that the trimeric have been shown to yield a with with the gp120 but the improvement is The 'native' of HIV and the difficulty in getting large of such a product has been to a safe are to protein that not modify the protein antigens have been One from and gag and a developed, the of needed to the HIV It is that a and inactivated HIV that is immunogenic from the combination of these a inactivated HIV based on a primary isolate was and purified with by the of Aventis Although this product effective neutralizing antibodies against the homologous primary HIV in neutralization of other primary HIV was not It is that this product will be in on 'native' envelope immunogens HIV envelope proteins are from the envelope protein not only results in a virus that is more neutralization but also an infectious that is and to the envelope epitopes can also be by from the gp120 with a of the envelope by with the protein itself has been shown to induce antibodies effective not only at neutralizing homologous but also effective at neutralizing a of heterologous primary and protein immunogens from a primary strain of subtype B with being developed by CA, are to be ready for human trial 2 years for AIDS vaccine clinical trial HIV envelope structure is and to with cellular the infection there are in the envelope protein that expose neutralization epitopes The why antibodies to these epitopes are not in HIV patients is that they 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