Important note: Information in this article was accurate in September/ November 2000. The state of the art may have changed since the publication date. IAVI Report - September / November 2000
Patricia Kahn
Even before the 12,700 delegates at this summer's XIII International Conference on AIDS had left for home, the meeting was already being hailed as a landmark event in the history of the epidemic. From the impassioned calls to bring treatment to PWAs in poor countries to the outrage over South African President Mbeki's espousal of AIDS "dissident" ideas, the meeting created a momentum which - if it truly lasts - will mark a turning point in the fight against AIDS.
The conference was also a landmark event for vaccine development, solidifying its place as a top priority in that battle, particularly in poor regions. Unlike earlier meetings of the series, where vaccines were largely a side issue, this year's event offered a profusion of vaccine-related sessions. With the dust now settled on the remarkable politics of Durban, the IAVI Report looks at some of the notable vaccine science and news presented there.
In this succinctly-titled plenary talk on vaccine development, Margaret Liu, former head of the HIV vaccine program at the Chiron Corp. (and now vaccine advisor to the Gates Foundation) outlined what she sees as the field's major achievements and most promising ways forward. Key items on her list were:
Liu said that the question posed in the title of her talk could not yet be answered, although she expressed confidence that good candidates will be in advanced trials by 2007. But getting an effective vaccine on this timescale will take both a greatly increased effort and a commitment to be guided by scientific data and "rational empiricism" rather than by biases, which she said can creep into issues such as the debate on subtypes (see below). She also emphasized the importance of pushing multiple vaccine approaches forward in parallel and of preparing trial sites so they are ready when the candidates are.
One major session focused on efforts to make vaccines targeted specifically to African needs and on vaccine work within Africa.
Immunologist Malegapuru William Makgoba, who heads South Africa's Medical Research Council, led with an overview of his country's HIV vaccine program, which has received strong government backing despite President Mbeki's questioning that HIV causes AIDS. The program is coordinated by the South African AIDS Vaccine Initiative (SAAVI), whose goal is the development of an affordable, subtype C-based vaccine owned by the public sector. SAAVI's scientific activities range from developing candidate vaccines (4 different approaches are now in the works) to immunological evaluation of vaccines and helping to prepare clinical trial sites. South Africa will also participate in testing candidates developed with international partners. The first one likely to enter clinical trials in the country is based on the Venezuelan equine encephalitis virus (VEE) vector made by AlphaVax, a North Carolina-based company, and funded by IAVI. Also under consideration are DNA vaccines from the Chiron Corporation and a vaccine from Targeted Genetics based on adeno-associated virus (AAV).
Carolyn Williamson of the University of Cape Town described how her lab derived subtype C sequences representative of southern African strains to use in the VEE vaccine. The researchers began by collecting samples from 14 commercial sex workers who were recent seroconverters and isolating virus from 10 of them. After confirming that these isolates infect cells via the CCR5 receptor, they sequenced 800 base pair regions from the gag, pol and env genes and compared them to over 70 known sequences from southern African subtype C strains, including some isolates from infected but asymptomatic individuals. In this way they arrived at 2 consensus sequences, which became the basis for this vaccine.
With Kenya now poised to launch Africa's second AIDS vaccine trial (see article), clinical investigator Dorothy Nbori-Ngacha of the University of Nairobi described the ongoing preparations. Efforts are now focused on finalizing the planning and oversight committees, such as the data safety and monitoring board, clinical steering committee and community advisory board, and getting the remaining scientific and ethical approvals. [Since the Durban conference, work is also focusing on patent and intellectual property issues; see www.iavi.org.]
Rounding out the session, Peter Mugyenyi, clinical director for Africa's first AIDS vaccine trial, described Uganda's long journey from the time of its early interest in AIDS vaccine development to the recently-completed trial at the Joint Clinical Research Center (JCRC) in Kampala (see below). Wayne Koff, who heads IAVI's R & D program, gave an update on IAVI-supported projects to develop AIDS vaccines geared to circulating African strains (see IAVI Report, Jan-Mar. 2000, p.5).
At a press conference following the above session, several African scientists, along with Jose Esparza of the WHO/UNAIDS HIV Vaccine Initiative, presented "The Nairobi Declaration: An African Appeal for an HIV Vaccine." They also unveiled the broad outline of a strategy to move the vaccine agenda forward within Africa and to achieve greater coordination across the continent. Signed by 38 African scientists, community advocates and policy makers, the statement came after a process that solicited the views of African researchers and then formulated a set of principles and proposals, which were adopted at a 14 June meeting in Nairobi under the auspices of WHO/UNAIDS, AfriCASO (an umbrella for African AIDS service organizations), the Southern African Development Community (SADC) and the Society on AIDS in Africa (SAA).
The strategy outlines 5 areas for activity: advocacy and education; coordination; promotion of promising candidate vaccines; building capacity to conduct trials; and ensuring access. It also lays out specific milestones, including the development of candidate vaccines based on African subtypes by 2002; completion of at least 4 Phase I/II trials by 2003; and initiation of at least one Phase III trial by 2005. South Africa's Makgoba described the initiative as a way for African scientists "to speak with one voice [and to] be responsible for our own future." Makgoba will help coordinate the effort, which is now working to turn the strategy into a specific action plan and to raise political support and funds for its activities.
VaxGen's first two HIV vaccine efficacy trials are now in full swing and have a combined enrollment of nearly 8000 volunteers. Several speakers presented data on the experiences and self-reported risk behaviors of these trial cohorts, with an apparent downward trend in risk behavior.
Kachit Choopanya of the Bangkok Metropolitan Administration gave an update on the VaxGen trial in Thailand. Participants were recruited among intravenous drug users at 17 methadone clinics in Bangkok. [On 31 August, VaxGen announced that enrollment of 2500 volunteers was complete.] The cohort is about 93% male and has an annual HIV seroincidence estimated at 6%, based on studies of a similar population over the years 1995-1999. Two-thirds of the volunteers will receive 7 doses of vaccine (made of recombinant gp120 subunit from two different HIV subtypes) over 24 months, while the rest will be given placebo. Choopanya also reported that retention in the trial is over 95% and that the vaccine is well-tolerated and immunogenic in all participants. Another trial investigator, Suphak Vanichseni of the Bangkok Vaccine Evaluation Group, presented interesting findings on trends in risk behaviors. Based on data from the 1174 volunteers who had reached their 6-month follow-up, she reported that the frequencies of nearly all risk behaviors (except recent incarceration) had dropped - some dramatically so -- since the trial began: the proportion of volunteers injecting drugs decreased from 72% to 57%; needle sharing fell from 32 to 13% and condom use increased from 51% to 62% with casual partners and from 8% to 12% with steady partners. Since such changes will lower HIV seroincidence, Vanichseni was asked whether the trial retains sufficient statistical power (it is designed to detect 30% vaccine efficacy). She responded that the study is powered for a reduction in seroincidence from 6% to 4% and that the cohort is still within that range, according to the Data Safety and Monitoring Board that is closely following the trial data.
Clayton Harro of Johns Hopkins University (Baltimore) reviewed the North America/Amsterdam trial, which is spread over more than 60 sites and is fully enrolled. Its 5414 volunteers are mostly men who have sex with men (MSM), along with 311 high-risk women. Annual seroincidence in the cohort is approximately 1.5%, and retention as of January 2000 was over 98%.
John Jermano of VaxGen presented data on the social impact of participation in the North America/Amsterdam trial, based on information reported by volunteers as of June 2000. The most frequent negative effects so far (reported by 7.5% of the participants at 6 months) are disturbances in relationships with family or friends, usually stemming from negative comments about participation or misperceptions that the volunteer is infected. Few volunteers (<1%) said they had experienced discrimination in employment or insurance due to their participation. Sexual risk behavior also decreased, with the median number of male partners reported by MSM during the past 6 months dropping from 5.0 (for the period prior to entering the trial) to 4.0 (during the first 6 months in the trial).
Jorge Flores (NIH, Bethesda) presented a potentially important finding concerning the adjuvant QS21, a saponin made from the soapbark tree and already used in veterinary vaccines. Reporting on a study by the NIH HIV trials network (study AVEG036) involving 60 volunteers, Flores said that 0.5 µ of VaxGen's bivalent gp120 vaccine (subtypes B/E) prepared in QS21 gave the same immune response as 300 µ in alum, the current adjuvant. This 600-fold reduction in the amount of antigen per dose would greatly cut the cost of the vaccine and make it far more economically feasible to produce polyvalent vaccines (containing gp120 subunits from multiple subtypes or strains, including breakthrough viruses). The trial also showed that a new formulation of QS21 reduced, but did not eliminate, the problem of relatively severe local reactions. According to study chair Tom Evans of the University of Rochester, a new trial is in planning to test whether reducing the amount of QS21 will reduce its reactogenicity but not its immune-enhancing effect.
In a late-breaker session, H. Cao of the Massachusetts General Hospital (Charlestown) presented results from a Phase I study of the ALVAC vCP205 canarypox HIV vaccine, conducted at the JCRC in Kampala and supported by the U.S. NIAID. The vaccine contains the gag and pol genes from HIV-1 subtype B. Several Phase I and II trials in the U.S.A. and France found it to be safe and to induce CTLs in a minority of volunteers. The Ugandan study enrolled 40 volunteers (20 immunized 4 times over 6 months with the test vaccine, 10 with rabies vaccine and 10 with placebo) and analyzed CTL responses against the vaccine antigens and against Gag and Pol from two non-matching subtypes, A and D.
Cao reported that immunogenicity was similar to earlier trials, with 4/20 of the volunteers positive for CTLs at some point during the study. In the 4 positive individuals, CTLs were no longer detectable 100 days after the last vaccination. CTLs in 2 of the 4 responders recognized subtypes A and/or D antigens (at about 80% of the level seen against B). Results were confirmed with the ELISPOT assay.
Luwy Musey from the University of Washington (Seattle) presented data showing that the ALVAC vCP205 vaccine can also induce mucosal responses. Although mucosal immunity is widely viewed as potentially important for protection, it has not been monitored so far in HIV vaccine trials. Musey analyzed immune responses in 12 participants of a Phase II study (AVEG202/ HIVNET014), 6 of whom had CTLs in the blood at some earlier point in the trial. Seven of these volunteers received vaccine and 5 received placebo. HIV-specific mucosal responses (measured by CTL in rectal tissue) were seen in 4/7 vaccinated people, with 2 of the 7 showing both blood and mucosal CTLs; 3/7 had CTLs only in the blood. Mucosal response was not affected by a gp120 boost. Results were confirmed with the ELISPOT assay.
In two talks, including a plenary lecture, Francine McCutchan of the Henry M. Jackson Foundation (Rockville, Maryland) reviewed the current state of knowledge about HIV variation and the challenge that continuous, rapid evolution of the HIV genome poses for vaccine development.
McCutchan pointed out that new molecular data are changing the view of how this diversity arises. While previously attributed mostly to HIV's high mutation rate, it is now emerging (from analysis of the many new full-length genome sequences becoming available) that recombination also plays a major role. Moreover, the likelihood of inter-subtype recombination is rising as subtypes continue to spread worldwide and more regions have multiple subtypes in circulation. (For example, non-B subtypes are increasingly seen in western countries, while 4 or more subtypes are common in parts of western Africa).
Based on analysis of 145 full-length sequences, 65 of them previously unreported, McCutchan described some important patterns. Many recombinants seem to be unique to one person, and some show an unexpectedly high complexity (e.g., an AFGJK recombinant). Other recombinants have entered the circulation in certain regions and are as common as some local subtypes; for instance, 56% of the circulating HIV in Cameroon is a circulating recombinant form (CRF) called CRF02.AG. Other examples include the AE strain in southeast Asia, a BC recombinant in China and an AB form in Russia's IDU population. In the latter group, where infection rates are skyrocketing, McCutchan noted the highly puzzling fact that there is little genetic diversification of the transmitted strain - a stark contrast to all non-IDU transmission chains that have been followed, including blood-borne chains such as the Florida dentist group or the Sydney blood transfusion cohort.
Addressing the implications of these findings for vaccine development, McCutchan said that comprehensive data on the pool of circulating strains is crucial for designing vaccines based on local strains, especially in regions with multiple subtypes. Without it, there is a danger of basing designs on a unique recombinant isolate rather than an important circulating strain. But the central issue for vaccines remains just how much the diversity of HIV sequences affects immune recognition of the encoded proteins, and consequently, whether vaccines based on one strain will protect against others.
Focusing on this uncertainty, an interesting debate session featured two speakers presenting opposing views on whether vaccines tested in the developing world should always be based on an important subtype in the host country.
Rosemary Musonda of the Tropical Diseases Research Center (Ndola, Zambia) made the case against requiring a match. There is ample evidence that vaccines based on one subtype can elicit immunity against other subtypes, she said, especially in terms of cellular immune responses. With the need for a vaccine so urgent, unnecessary restrictions on trials should be avoided. And it is only by testing such "mismatches" that the true relevance of subtype to vaccine efficacy can be clearly determined.
Arguing the other side, Carolyn Williamson of the University of Cape Town stated that neutralizing antisera from HIV-infected people appear to work better against virus of the same subtype than against unmatched subtypes. Such data suggest that matching will maximize the chances of success for a candidate vaccine. It may also contribute to community acceptance of vaccine trials, since it sends a message that the test vaccines are genuinely geared to local needs.
During the discussion, audience members raised some key questions. If a matched vaccine proves to be effective in a Phase III trial, what's next? Will countries with other subtypes in circulation have to repeat the trial? And what if new subtypes or recombinants enter the region, or vaccinated people move to areas where different subtypes predominate? Matched trials will not test whether there is protection under these circumstances. Session moderator Peggy Johnston of the U.S. NIAID made the crucial point that even if a vaccinee responds less strongly to an unmatched HIV subtype, this weaker response might still be enough to protect. Vaccinologist Don Burke of Johns Hopkins University (Baltimore) responded that a similar dilemma facing developers of a vaccine against Japanese encephalitis virus was addressed by a Phase III trial with three arms: matched vaccine, unmatched and placebo. It is likely that HIV vaccine trials will ultimately require a similarly systematic approach.
Clinical studies of people exposed to HIV but seronegative (ESN), which have been done mostly in commercial sex workers, have pointed to key role for cellular immunity in this apparent protection. Lawal Garba of the University of North Carolina (Chapel Hill) presented new ESN data from a collaborative study of discordant couples in Zambia. Looking at 37 ESN individuals (all married or in steady partnerships with infected people for at least 3 years), the researchers found HIV-specific CTL in 9 of them. Intriguingly, the presence of CTL was correlated with high viral load in the infected partner, suggesting that total antigen dose may be an important aspect of stimulating CTLs.
Y.-M. Chen (Taipei) reported an observation which could imply the presence of enhancing antibodies to Tat in some HIV-positive people. (For a discussion of enhancing antibodies, see IAVI Report, April-June 2000, p.5). The researchers looked at transmission to the wives of 52 HIV-positive men drawn from blood bank donors who became infected primarily through contact with commercial sex workers. Among 52 men, 1 of 17 infected with subtype B, 14 of 33 with subtype E and 2 of 2 with subtype C transmitted virus to their wives. The transmitters had a higher level of anti-Tat antibody than non-transmitters (65% vs 26%), as determined by ELISA tests. The odds ratio of men infected with subtype E transmitting to their wives if they also had anti-Tat antibodies was extremely high (OR=18). The researchers are now analyzing whether anti-Tat antibodies might selectively enhance infectivity of different HIV subtypes. All current Tat vaccines have used subtype B tat genes, and enhancement of transmission has not been previously reported.
000910
IAVI2000-090105
©2000. The IAVI Report.
ÆGiS is made possible through unrestricted grants from Roxane Laboratories, Inc., iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.
ÆGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2000. ÆGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on ÆGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of ÆGIS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.
