Content uploaded by Amy Sheon
Author content
All content in this area was uploaded by Amy Sheon on Aug 22, 2018
Content may be subject to copyright.
Preparing for HIV vaccine efficacy trials: Partnerships and challenges
Abstract
Initiation of clinical efficacy trials of candidate human immunodeficiency virus (HIV) vaccines may be scientifically and ethically warranted in the next few years. The National Institute of Allergy and Infectious Diseases (NIAID) is making preparations to start trials with minimal delay as soon as a suitable candidate vaccine becomes available. NIAID is sponsoring the establishment of an infrastructure for epidemiological studies of populations at potential sites for such trials. In field trials, we will need to measure suitable end points-infection, immunological status, and clinical status- necessary to judge vaccine effectiveness in preventing infection and/or disease. Difficulties in recruiting and following high-risk populations present a major research challenge. The many scientific, ethical, social, legal, and political issues related to such trials are being addressed in partnership with many groups, both in the United States and abroad. This partnership must include the public and private sectors: communities experiencing epidemic HIV spread, companies developing candidate vaccines, U.S. and international agencies, universities, and governments. Effective HIV prevention will require persistent attention to behavior change, including partner reduction and condom use, even as we develop and test candidate vaccines to prevent HIV and the acquired immunodeficiency syndrome (AIDS).
... The HIV Network for Prevention Trials (HIVNET) was formed in 1993 to conduct domestic and international multi-center trials to evaluate the safety and efficacy of promising HIV preventive interventions including, but not limited, to vaccines. To prepare for international vaccine trials, in 1993 the NIH launched the "Preparation for AIDS/HIV Vaccine Evaluation" (PAVE) projects, with international sites in Haiti, India, Kenya, Malawi, Rwanda, Thailand, Uganda, and Zimbabwe [141]. ...
Soon after HIV was discovered as the cause of AIDS in 1983-1984, there was an expectation that a preventive vaccine would be rapidly developed. In trying to achieve that goal, three successive scientific paradigms have been explored: induction of neutralizing antibodies, induction of cell mediated immunity, and exploration of combination approaches and novel concepts. Although major progress has been made in understanding the scientific basis for HIV vaccine development, efficacy trials have been critical in moving the field forward. In 2009, the field was reinvigorated with the modest results obtained from the RV144 trial conducted in Thailand. Here, we review those vaccine development efforts, with an emphasis on events that occurred during the earlier years. The goal is to provide younger generations of scientists with information and inspiration to continue the search for an HIV vaccine.
A vaccine to prevent HIV infection or disease would be a great benefit to the global community. Efforts in the development of such a preventive vaccine have been hampered by a number of formidable scientific, logistic, ethical, and political challenges, yet scientists remain optimistic about the possibility. The state of the science as of early 1995 has been summarized in this article. A growing number and variety of vaccine concepts and products are being tested in animals and humans (including, for example, pseudovirions, naked DNA, and live attenuated mutants, with specific gene deletions, among others). Trials are exploring whether changing immunization schedules, increasing booster doses, or using a combination vaccine strategy can stimulate stronger, durable immune responses. Progress in basic and clinical research and advances in molecular biology, genetics, and technology continue to create promising opportunities for vaccines.
Questions exist about whether testing of preventive human immunodeficiency virus (HIV)-1 vaccines, which will require rapid recruitment and retention of cohorts with high HIV-1 seroincidence, is feasible in the United States. A prospective cohort study was conducted in 1995-1997 among 4,892 persons at high risk for HIV infection in nine US cities. At 18 months, with an 88% retention rate, 90 incident HIV-1 infections were observed (1.31/100 person-years (PY), 95% confidence interval (Cl): 1.06, 1.61). HIV-1 seroincidence rates varied significantly by baseline eligibility criteria-1.55/100 PY among men who had sex with men, 0.38/100 PY among male intravenous drug users, 1.24/100 PY among female intravenous drug users, and 1.13/100 PY among women at heterosexual risk-and by enrollment site, from 0.48/100 PY to 2.18/100 PY. HIV-1 incidence was highest among those men who had sex with men who reported unprotected anal intercourse (2.01/100 PY, 95% CI: 1.54, 2.63), participants who were definitely willing to enroll in an HIV vaccine trial (1.96/100 PY, 95% Cl: 1.41, 2.73), and women who used crack cocaine (1.62/100 PY, 95% CI: 0.92, 2.85). Therefore, cohorts with HIV-1 seroincidence rates appropriate for HIV-1 vaccine trials can be recruited, enrolled, and retained.
: Evaluation of HIV vaccines requires high-risk individuals willing to participate in a vaccine trial. We investigated the willingness to participate in HIV vaccine trials of initially HIV-seronegative homosexual men enrolled in an HIV seroincidence cohort study. Of 815 initially HIV-seronegative participants, 569 (69.8%) reported willingness to participate in an HIV vaccine trial. Altruism was the primary reason given for wanting to participate. Fear of HIV infection from the study's immunizations and a vaccine-induced positive HIV test result were the main reasons for not wanting to participate. Of the 34 study subjects who eventually had HIV seroconversion, 29 (85%) had indicated a willingness to participate. In a univariate analysis, factors associated with willingness to participate included HIV seroconversion during followup (odds ratio [OR]. 2.6; p = .04), low educational level (OR, 1.6; p = .005), low family income (p = .02), and exchanging sex for housing, food, or clothing (OR 6.1; p = .005). Students were less likely to be willing to participate in a trial (OR, 0.7; p = .03), as well as those who reported sex at the first encounter (OR, 0.7; p = .05). In a multivariate analysis, low education level, infection with Condyloma, and exchanging sex for housing, food, or clothing were positively associated with willingness to participate, whereas being a student and reporting sex at first encounter were negatively associated. In general, factors indicative of high-risk of HIV infection were associated with a higher willingness. These data demonstrate that this high-risk homosexual male cohort has a high willingness to participate in HIV vaccine trials.
(C) 2000 Lippincott Williams & Wilkins, Inc.
Recent studies have reported on the utility of audio computer-assisted self-interviewing (ACASI) in surveys of human immunodeficiency virus (HIV) risk behaviors that involve a single assessment. This paper reports the results of a test of ACASI within a longitudinal study of HIV risk behavior and infection. Study participants (gay men ( n = 1,974) and injection drug users ( n = 903)) were randomly assigned to either ACASI or interviewer-administered assessment at their second follow-up visit 12 months after baseline. Significantly more of the sexually active gay men assessed via ACASI reported having sexual partners who were HIV antibody positive (odds ratio = 1.36, 95% confidence interval: 1.08, 1.72), and a higher proportion reported unprotected receptive anal intercourse. Among injection drug users (IDUs), our hypothesis was partially supported. Significantly more IDUs assessed via ACASI reported using a needle after another person without cleaning it (odds ratio = 2.40, 95% confidence interval: 1.34, 4.30). ACASI-assessed IDUs reported similar rates of needle sharing and needle exchange use but a lower frequency of injection. Participants reported few problems using ACASI, and it was well accepted among members of both risk groups. Sixty percent of the participants felt that the ACASI elicited more honest responses than did interviewer-administered questionnaires. Together, these data are consistent with prior research findings and suggest that ACASI can enhance the quality of behavioral assessment and provide an acceptable method for collecting self-reports of HIV risk behavior in longitudinal studies and clinical trials of prevention interventions.
Clinical research on HIV-1 vaccine candidates, which began less than a decade ago, illustrates many facets of vaccine trials in general. At each step, however, from gaining public acceptance for the trial and recruiting volunteers to evaluation of data, unique problems have arisen. In this chapter, we will discuss clinical evaluation of HIV-1 vaccines as both a paradigm and a special case of vaccine clinical trials. We will emphasize prophylactic use of vaccines.
Infection with HIV results in lifelong persistence of virus in infected cells. It also induces an immune response against the virus which is substantial and of a broad spectrum. Yet, the progression to immune deficiency and clinical disease is inexorable. It has been a normal practice of developing a vaccine for the control of any communicable disease whose agent has been isolated and characterised. It is much more expedient to develop a vaccine for control of AIDS, because we are still far away from effective antiviral therapy. A safe and effective HIV vaccine would be an important addition to present, and future prevention strategies and the vaccine must elicit an immune state which will prevent the establishment of the HIV persistent infection. Two distinct types of viruses responsible for AIDS have been defined : HIV-1 and HN-2. HIV-2 is responsible for AIDS in West Africa, while HIV-1 has caused AIDS epidemic in Central Africa and the rest of the world. With modern communication lines, spread of HIV-2 to other regions cannot be ruled out? HIV are retroviruses and the genomes of
The purpose of this study was to assess the willingness of intravenous drug users to participate in a preventive human immunodeficiency virus (HIV) vaccine efficacy trial.
Of the 347 intravenous drug users in methadone treatment who were approached for participation, 257 completed a battery of self-administered questionnaires assessing risk behaviors, interest in vaccine trials, and other vaccine-related information. Data from 16 known seropositives and 1 inconsistent responder were dropped from analyses (n = 240).
Fifty-two percent of the subjects expressed a willingness to be one of the first individuals to participate in a preventive HIV vaccine efficacy trial. Subjects who had recently shared needles or works and subjects who trusted the government to ensure vaccine safety were both twice as likely to report interest in participation. Twenty-two percent of subjects reported that they would increase needle sharing if vaccinated. Thirty percent did not know what a vaccine was.
These findings suggest that some in-treatment intravenous drug users would volunteer for a preventive HIV vaccine efficacy trial. Education and counseling will be required to ensure that subjects fully understand the trial's purposes, methods, risks and benefits.
To estimate interest in HIV preventive vaccine trials, we administered questionnaires to two otherwise demographically similar cohorts of older (mean 40 years) and younger (mean 23 years) gay men in Boston. Questionnaire responses were linked to concurrent behavioral and demographic data. Univariate analyses, performed separately for older and younger cohorts, identified factors that distinguished participants who were "very interested" from those who were "not at all interested". Multivariate logistic regression analyses were used to adjust for confounding. Among all 630 participants, 215 (34%) were "not at all" interested in participating, 306 (49%) were "somewhat" interested, and 102 (16%) were "very" interested. Older men were significantly more likely than younger men to be "very" interested and less likely to be "not at all interested." Among both older and younger men, perceived peer willingness to enroll in vaccine trials predicted interest after adjusting for confounding. Among older men, optimism about success in vaccine development also predicted interest. In the younger cohort, men recruited in community settings (e.g., bars, nightclubs) were more interested in vaccine trial participation than were those recruited by outreach workers and word of mouth on college campuses. Vaccine-induced seroconversion evoked significant concern.
Acquired immunodeficiency syndrome (AIDS) and human immuno-deficiency virus (HIV) are growing problems among U.S. adolescents. By examining recent data on AIDS surveillance and HIV seroprevalence, surveys on teenagers' knowledge, beliefs, and behaviors related to HIV/AIDS, key treatment issues, and barriers to prevention, this manuscript reviews the problem and proposes possible ways of combating it. African American youth have the highest rates of AIDS and white youth the lowest. However, the largest number of AIDS cases overall has been recorded in white males, reflecting relatively high case rates in boys with hemophilia and in young male homosexuals. Predominant HIV risk factors for adolescents are unprotected sex and/or sharing injection drug equipment with an infected partner. Relatively high rates of HIV infection in adolescent females may indicate their greater physiological vulnerability than adult females to sexually transmitted diseases (STDs). Data from HIV seroprevalence studies suggest a substantially increased heterosexual epidemic in the 1990s, especially in large east coast cities and southeastern rural areas where drug use and/or STDs are highly prevalent. More comprehensive prevention and treatment services are needed to prevent on-going expansion of HIV infection and AIDS in the adolescent age group.
The pathogenesis and clinical expression of HIV-1 infection in humans is considered in terms of classical pathogenetic studies of viral infections for which successful vaccines have been produced. The unique features of HIV pathogenesis are defined, and gaps in knowledge identified as a framework for considering designs for immune intervention. Envelope-derived candidate vaccines have been used in immunization and challenge experiments in SIV/macaque or HIV/chimpanzee models, presented either as vaccinia recombinant vectors or as subunits, singly or in sequence. These studies have been paralleled by clinical trials for safety and immunogenicity in seronegative individuals. Data generated will permit comparison of immune responses to specific antigens and delivery systems in animal models and in humans. In limited studies conducted under optimized conditions, non-human primates have been protected against virus challenge when immunized with some candidate vaccines or following passive transfer of high-titred antibody. Consideration of current information suggests that in order to prevent HIV infection it may be necessary to devise new strategies capable of inducing and maintaining high threshold titres of biologically relevant antibody as well as persistence of active cytotoxic T cells recognizing multiple epitopes.
In the United States, an increasing proportion of women infected with the human immunodeficiency virus (HIV) live in nonmetropolitan areas. Little is known, however, about the risk factors for HIV transmission in women outside large cities.
We interviewed and tested 1082 (99.8 percent) of 1084 consecutive pregnant women who registered for prenatal care at a public health clinic in western Palm Beach County, Florida. This rural agricultural area of about 36,000 people is known to have a high prevalence of HIV infection.
The seroprevalence of HIV was 5.1 percent (52 of 1011 women). Black women who were neither Haitian nor Hispanic had the highest rate of infection (8.3 percent [48 of 575]). Only 4 of 1009 women (0.4 percent) reported ever injecting drugs, and the 4 were HIV-seronegative; however, 14 of 43 users of "crack" cocaine (33 percent) had HIV infection. At prenatal registration, 131 of 983 women (13 percent) tested positive for gonorrhea, chlamydial infection, or syphilis. By multivariate logistic-regression analysis, HIV infection was found to be independently associated with having used crack cocaine (odds ratio, 3.3; P < 0.001), having had more than two sexual partners (odds ratio, 4.6; P < 0.001), being black but neither Hispanic nor Haitian (odds ratio, 11; P < 0.001), having had sexual intercourse with a high-risk partner (odds ratio, 5.6; P < 0.001), and testing positive for syphilis (odds ratio, 3.1; P = 0.015). Nevertheless, 11 of the 52 HIV-infected women (21 percent) reported a total of only two to five sexual partners and no known high-risk partners, had never used crack cocaine, and had no positive tests for sexually transmitted disease.
In the rural community we studied, most of the women with HIV infection acquired it through heterosexual contact. The increasing seroprevalence of HIV and the increasing incidence of syphilis and use of crack cocaine mean that other women may be at similar risk of acquiring heterosexually transmitted HIV infection.
A titer for homologous viral neutralization activity (greater than 1:19,683) was observed after a 3.5-year immunization period with an octameric, branching peptide representing the principal neutralizing determinant (PND) of the human immunodeficiency virus-1IIIB envelope protein. Booster immunizations elicited persistent and potent antibodies in guinea pigs, exceeding responses produced by a conventional bovine serum albumin conjugate by 100-fold. Peptide length, central presentation of a conserved sequence, and inclusion of an upstream sequence contributed to immunogenicity. Titers (greater than 1:1,000) of heterotypic neutralizing antibodies also developed. Octameric PND peptides are a promising approach for an acquired immunodeficiency syndrome (AIDS) vaccine.
Recent advances in delineating the molecular biology of human immunodeficiency virus type 1 (HIV-1) have led to innovative approaches to development of a vaccine for acquired immunodeficiency syndrome (AIDS). However, the lack of understanding of mechanisms of protective immunity against HIV-1, the magnitude of genetic variation of the virus, and the lack of effective animal models for HIV-1 infection and AIDS have impeded progress. The testing of AIDS vaccines also presents challenges. These include liability concerns over vaccine-related injuries; identification of suitable populations for phase 3 efficacy studies; balancing the ethical obligation to counsel research subjects to avoid high-risk behavior with the necessity to obtain vaccine efficacy data; and the effect of vaccine-induced seroconversion on the recruiting and welfare of trial volunteers. Several candidate AIDS vaccines are nevertheless currently under development, and some are undergoing phase 1 clinical trials. Rapid progress will depend on continued scientific advancement in conjunction with maximum use of resources, open information and reagent exchange, and a spirit of international collaboration.
We assessed the efficacy of an inactivated hepatitis B vaccine in a placebo-controlled, randomized, double-blind trial in 1083 homosexual men known to be at high risk for hepatitis B virus infection. The vaccine was found to be safe and the incidence of side effects was low. Within two months, 77% of the vaccinated persons had high levels of antibody against the hepatitis B surface antigen. This rate increased to 96% after the booster dose and remained essentially unchanged for the duration of the trial. For the first 18 months of follow-up, hepatitis B or subclinical infection developed in only 1.4 to 3.4% of the vaccine recipients as compared with 18 to 27% of placebo recipients (P < 0.0001). The reduction of incidence in the vaccinees was as high as 92.3%; none of the vaccinees with a detectable immune response to the vaccine had clinical hepatitis B or asymptomatic antigenemia. A significant reduction of incidence was already seen within 75 days after randomization; this observation suggests that the vaccine may be efficacious even when given after exposure.