Improved outlook on HIV-1 prevention and vaccine development

Introduction: The development of an effective vaccine against HIV-1 has been challenging but recent advances in both the HIV prevention landscape and the partial efficacy of the recent RV144 vaccine efficacy trial in Thailand provide hope for an improved arsenal of approaches to prevent HIV-1 transmission.

Areas covered: This review describes recent advances in HIV-1 prevention such as circumcision, microbicides and pre-exposure prophylaxis with antiretroviral therapy, but focuses mainly on the current state of HIV-1 vaccine development in the post-RV144 era.

Expert opinion: The field of HIV-1 vaccine development has been plagued by the unprecedented challenges involved with designing a vaccine effective in preventing transmission of a retrovirus, due in part to sequence diversity, retroviral integration into host chromosomes, establishment of reservoir sites and glycosylation shielding of the HIV-1 envelope. The partial efficacy of the recent RV144 vaccine trial in Thailand may allow for better understanding of immune correlates of infection risk, which could enable iterative improvements to vaccine regimens in the development pipeline. In parallel, a number of promising vaccine strategies incorporating viral vectors, novel immunogens, delivery systems and adjuvants are advancing in clinical development. Vaccine development must occur in parallel with continued advances in HIV-1 prevention.     

Current views on the potential for development of a HIV vaccine

Introduction: Despite many recent advances in the HIV prevention landscape, an effective vaccine remains the most promising tool to end the HIV-1 pandemic.

Areas covered: This review summarizes past HIV vaccine efficacy trials and current vaccine strategies as well as new approaches about to move into first-in-human trials.

Expert opinion: Despite many setbacks in early HIV vaccine efficacy trials, the success of RV144 has provided the glimmer of hope necessary to invigorate the vaccine field, and has led to the development of a large number of vaccine strategies aiming at inducing an array of different immune responses. The follow-up pox-protein trials, developed to replicate and enhance the polyfunctional antibody responses induced by the RV144 regimen, are already reaching efficacy trials, while a large body of work providing a more complete understanding of the development of broadly neutralizing antibodies is now being translated into immunogen design using several different strategies. T-cell based vaccines, fallen out of favor after Ad5-based trials showed increased infection rates in Ad5 seropositive vaccine recipients, are experiencing a comeback based in part on the promising results from non-human primate challenge studies using rhCMV-based immunogens. This diverse array of vaccine candidates may finally allow us to identify a broadly effective HIV vaccine able to contain the epidemic.     

FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial

The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1–specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor–mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2C SNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT-carrying vaccine recipients only. These data suggest a potent role of Fc-γ receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial.     

Maternal HIV-1 envelope–specific antibody responses and reduced risk of perinatal transmission

Despite the wide availability of antiretroviral drugs, more than 250,000 infants are vertically infected with HIV-1 annually, emphasizing the need for additional interventions to eliminate pediatric HIV-1 infections. Here, we aimed to define humoral immune correlates of risk of mother-to-child transmission (MTCT) of HIV-1, including responses associated with protection in the RV144 vaccine trial. Eighty-three untreated, HIV-1–transmitting mothers and 165 propensity score–matched nontransmitting mothers were selected from the Women and Infants Transmission Study (WITS) of US nonbreastfeeding, HIV-1–infected mothers. In a multivariable logistic regression model, the magnitude of the maternal IgG responses specific for the third variable loop (V3) of the HIV-1 envelope was predictive of a reduced risk of MTCT. Neutralizing Ab responses against easy-to-neutralize (tier 1) HIV-1 strains also predicted a reduced risk of peripartum transmission in secondary analyses. Moreover, recombinant maternal V3–specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus, common V3-specific Ab responses in maternal plasma predicted a reduced risk of MTCT and mediated autologous virus neutralization, suggesting that boosting these maternal Ab responses may further reduce HIV-1 MTCT.     

Challenges in the development of an effective HIV vaccine: current approaches and future directions

OBJECTIVE: The intent of this review is to investigate and discuss why developing a successful HIV vaccine has been so challenging, first by examining the molecular biology of the virus and how HIV interacts with the immune system, and then reviewing past viral vaccine successes as well as future directions for HIV vaccine research. BACKGROUND: Since HIV appeared in the United States in the early 1980s, an estimated 40 million people worldwide have been infected with the virus. Despite promising advances in the pharmacotherapy of HIV infection, it is apparent that the best, most cost-effective strategy for controlling the further spread of the virus is through synthesis of a protective vaccine. Almost 2 decades into the epidemic, there are few prospects for a truly effective vaccine entering the market in the foreseeable future. METHODS: MEDLINE was searched for articles written between 1966 and June 1999. Search terms used were AIDS, HIV vaccine, HIV-1, HIV-2, vaccines, and human immunodeficiency virus. RESULTS: Only 2 candidates for an HIV vaccine are currently in phase III clinical trials (1 in the United States and 1 in Thailand). The efficacy of these vaccines when applied to the population as a whole is widely questioned, largely because they induce protection by an antibody response only. Several studies have suggested that this approach will likely be ineffective in providing any real protection from viral infection. It appears that a strong cellular immune response is necessary in addition to a strong antibody response.     

Development of HIV vaccines

An effective prophylactic vaccine should reduce frequency of new HIV infections in the target population and delay onset of immunodeficiency among those who become infected after vaccination. A variety of vaccine candidates have been developed, which induce neutralizing antibodies and/or cytotoxic T-lymphocytes. While many of those vaccine candidates exhibited some efficacy in primate model systems, their efficacy against natural HIV-1 infection can only be determined in large-scale phase III clinical trials. In this article, difficulties in HIV vaccine development will be discussed from scientific, technical, and business point of views.     

Combinatorial approaches to the prevention and treatment of HIV-1 infection

The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4+ T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development, in vitro and in vivo efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.     

Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent

Because both HIV-1 virions and HIV-infected cells are present in the semen and cervical mucus of infected individuals, HIV-1 prevention strategies must consider both cell-free and cell-associated virus. Antibodies that target HIV-1 virions have been shown to prevent vaginal transmission of cell-free virus in macaques, but since cell-associated transmission has not been reliably demonstrated in this model system, no strategies to prevent such transmission have been tested. We have employed a mouse model in which SCID mice carry human peripheral blood leukocytes (HuPBLs). In these mice, vaginal transmission of cell-associated, but not cell-free, HIV-1 transmission occurs, mediated by transepithelial migration of HIV-infected cells. Topical application of beta-cyclodextrin (beta-CD), a cholesterol-sequestering agent that interferes with cell migration and budding of virus from lipid rafts, blocks transmission of cell-associated HIV-1. The HuPBL-SCID model of vaginal HIV-1 transmission should prove useful for investigating cell-associated HIV-1 transmucosal HIV-1 transmission, as well as for screening reagents for their potential efficacy in preventing sexual HIV-1 transmission.     

New Insights on Adenovirus as Vaccine Vectors

Adenovirus (Ad) vectors were initially developed for treatment of genetic diseases. Their usefulness for permanent gene replacement was limited by their high immunogenicity, which resulted in rapid elimination of transduced cells through induction of T and B cells to antigens of Ad and the transgene product. The very trait that excluded their use for sustained treatment of genetic diseases made them highly attractive as vaccine carriers. Recently though results showed that Ad vectors based on common human serotypes, such as serotype 5, may not be ideal as vaccine carriers. A recently conducted phase 2b trial, termed STEP trial, with an AdHu5-based vaccine expressing antigens of human immunodeficiency virus 1 (HIV-1) not only showed lack of efficacy in spite of the vaccine''s immunogenicity, but also suggested an increased trend for HIV acquisition in individuals that had circulating AdHu5 neutralizing antibodies prior to vaccination. Alternative serotypes from humans or nonhuman primates (NHPs), to which most humans lack pre-existing immunity, have been vectored and may circumvent the problems encountered with the use of AdHu5 vectors in humans. In summary, although Ad vectors have seen their share of setbacks in recent years, they remain viable tools for prevention or treatment of a multitude of diseases.     

The vertical transmission of human immunodeficiency virus type 1: molecular and biological properties of the virus

The vertical (mother-to-infant) transmission of human immunodeficiency virus type 1 (HIV-1 ) occurs at an estimated rate of more than 30% and is the major cause of AIDS in children. Numerous maternal parameters, including advanced dinical stages, low CD4+ lymphocte counts, high viral load, immune response, and disease progression have been implicated in an increased risk of vertical transmission. While the use of antiretroviral therapy (ART) during pregnancy has been shown to reduce the risk of vertical transmission, selective transmission of ART-resistant mutants has also been documented. Elucidation of the molecular mechanisms of vertical transmission might provide relevant information for the development of effective strategies for prevention and treatment. By using HIV-1 infected mother-infant pairs as a transmitter-recipient model, the minor genotypes of HIV-1 with macrophage-tropic and non-syncytium-inducing phenotypes (R5 viruses) in infected mothers were found to be transmitted to their infants and were initially maintained in the infants with the same properties. In addition, the transmission of major and multiple genotypes has been suggested. Furthermore, HIV-1 sequences found in non-transmitting mothers (mothers who failed to transmit HIV-1 to their infants in the absence of ART) were less heterogeneous than those from transmitting mothers, suggesting that viral heterogeneity may play an important role in vertical transmission. In the analysis of other regions of the HIV-1 genome, we have shown a high conservation of intact and functional gag p17, vif, vpr, vpu, tat, and nef open reading frames following mother-to-infant transmission. Moreover the accessory genes, vif and vpr, were less functionally conserved in the isolates of non-transmitting mothers than transmitting mothers and their infants. We, therefore, should target the properties of transmitted viruses to develop new and more effective strategies for the prevention and treatment of HIV-1 infection.     

HIV-1 vaccines and co-infection

Vaccines are an economically efficient means of controlling viral infections, and it is likely that a vaccine against HIV-1 will be the most effective way of controlling the global AIDS crisis. However, an effective vaccine has not yet been attainable and in developing countries co-infection with protozoa and other chronic diseases adds another level of complexity to the design of an HIV-1 vaccine. Helminthic and protozoan infections can result in a constant state of immune activation that is characterised by a dominant T helper (Th)2 type of cytokine profile. Such an immune profile is likely to have an adverse impact on the efficacy of an HIV-1 vaccine CD8 cellular immune response and the corresponding Th1 cytokines that are most likely to be important for clearing viral infections.     

Infectious disease markers in blood donors in northern Thailand

BACKGROUND: A major epidemic of human immunodeficiency virus type 1 (HIV-1) infections that are primarily due to heterosexual transmission has developed in Thailand since 1988. The epidemic has been most severe in northern Thailand. The blood banks in Chiang Mai began screening donors for HIV-1 antibodies in February 1988 and for p24 antigen in April 1992. STUDY DESIGN AND METHODS: The trends of HIV-1 antibody prevalence were analyzed by type of donor (i.e., paid, replacement, and voluntary) for the period of 1988 through 1993. In addition, the prevalence of HIV-1 p24 antigen and of antibodies to syphilis, hepatitis B surface antigen, and hepatitis C virus was evaluated among blood donors at Chiang Mai University Hospital and the Thai Red Cross blood banks in Chiang Mai. RESULTS: The prevalence of HIV-1 antibodies increased from 0.84 percent in 1988 to 4.04 percent in 1991. Seropositivity was highest in paid professional donors. After discontinuation of the use of paid donors in 1993, HIV-1 antibody prevalence decreased to 3.34 percent. Antibody prevalence in replacement donors increased from 0.56 percent in 1988 to 5.82 percent in 1991. Among 44,446 donors tested, 7 (0.016%) were HIV-1 p24 antigen positive but antibody negative. CONCLUSION: The exclusion of paid donors and the use of p24 antigen testing are justified in northern Thailand. Additional strategies to exclude donors at very high risk and to attract those at low risk for infection should be developed and evaluated to increase blood transfusion safety in this and other, similar populations.     

HIV-1 vaccines and co-infection

Vaccines are an economically efficient means of controlling viral infections, and it is likely that a vaccine against HIV-1 will be the most effective way of controlling the global AIDS crisis. However, an effective vaccine has not yet been attainable and in developing countries co-infection with protozoa and other chronic diseases adds another level of complexity to the design of an HIV-1 vaccine. Helminthic and protozoan infections can result in a constant state of immune activation that is characterised by a dominant T helper (Th)2 type of cytokine profile. Such an immune profile is likely to have an adverse impact on the efficacy of an HIV-1 vaccine CD8 cellular immune response and the corresponding Th1 cytokines that are most likely to be important for clearing viral infections.     

Development of attenuated H5N1 avian influenza vaccines using reverse genetic technology

Outbreaks caused by highly pathogenic H5N1 avian influenza viruses have spread worldwide and the containment is impossible no longer. During the outbreaks, over 200 human infection cases with 55% fatality are confirmed at the moment and some human-to -human transmission in family clusters have been observed in Vietnam, Thailand and Indonesia. The potency of pandemic caused by highly pathogenic H5N1 avian influenza is increasing gradually. Consequently, development of effective H5N1 vaccine and its licensing for vaccination to human are urgent countermeasures for pandemic preparedness. In the present article, the author reviews the development of H5N1 attenuated vaccine by reverse genetic technology and discuss the problems on the vaccine production to be dissolved before pandemic occur.     

The spread, treatment, and prevention of HIV-1: evolution of a global pandemic

The most up-to-date estimates demonstrate very heterogeneous spread of HIV-1, and more than 30 million people are now living with HIV-1 infection, most of them in sub-Saharan Africa. The efficiency of transmission of HIV-1 depends primarily on the concentration of the virus in the infectious host. Although treatment with antiviral agents has proven a very effective way to improve the health and survival of infected individuals, as we discuss here, the epidemic will continue to grow unless greatly improved prevention strategies can be developed and implemented. No prophylactic vaccine is on the horizon. However, several behavioral and structural strategies have made a difference--male circumcision provides substantial protection from sexually transmitted diseases, including HIV-1, and the application of antiretroviral agents for prevention holds great promise.     

血液系统恶性肿瘤多肽类疫苗的研究进展

近年来血液系统恶性肿瘤的治疗有了显著进展,但由于微小残留病灶(MRD)的存在,复发仍是亟待解决的主要问题。肿瘤多肽疫苗是有望克服MRD的免疫疗法之一。本文重点介绍血液系统恶性肿瘤中WT1、RHAMM、BCR-ABL、PR1多肽疫苗的最新临床试验结果,PRAME、Survivin等多肽的特异性免疫反应新进展,及不规则肽疫苗、新型免疫佐剂、结合肽疫苗、Ad-tWT1疫苗等增强疫苗免疫治疗效应的最新措施及其应用前景。     

The diagnosis,transmission and prevention of HIV-1 in the infant under 18 months of age: implications for nursing practice

? Vertical transmission of HIV from mother-to-child is a significant problem around the world. This paper examines the main issues that confront those caring for pregnant women who may transmit HIV-1 to their babies with reference to the impact upon clinical practice. ? Nursing practice should accommodate research from a number of disciplines including medical and scientific researchers. ? A number of risk factors for vertical transmission have been identified, including immunological status of the mother, premature birth, method of delivery and breast feeding. ? The use of prophylactic zidovudine has also been shown to reduce the rate of transmission of the virus, although it is not clear at what point in pregnancy and delivery it exerts this protection. ? Although this paper considers recent advances in the prevention of vertical transmission, this is a rapidly developing area and readers are provided with Internet addresses where the most up to date information may be found.     

HIV-1 Immunogen: an overview of almost 30 years of clinical testing of a candidate therapeutic vaccine

ABSTRACT

Introduction: Although current antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable disease, ART does not cure HIV infection. Furthermore, the majority of the world’s infected individuals live in resource-limited countries in which access to ART is limited. Thus, the development of an effective therapeutic HIV vaccine would be an invaluable treatment alternative.

Areas covered: Developed by the late Dr. Jonas Salk, HIV-1 Immunogen (Remune®) is a candidate therapeutic vaccine that has been studied in thousands of HIV-infected individuals in more than a dozen clinical trials during almost three decades. This Drug Evaluation, which summarizes the results of these trials that have shown the vaccine to be safe and immunogenic, also discusses the contradictory and controversial conclusions drawn from the phases 2, 2/3 and 3 trials that assessed the clinical efficacy of this vaccine.

Expert opinion: Given the lack of unequivocal clinical benefits of HIV-1 Immunogen despite almost 30 years of extensive testing, it does not appear, in our view, that this vaccine is a clinically effective immunotherapy. However, inclusion of this vaccine in the newly proposed ‘Kick/Shock and Kill’ strategy for HIV eradication, or use as a prophylactic vaccine, could be considered for future trials.     

Starting from scratch: program development and lessons learned from HIV vaccine trial counseling in Thailand

Counseling for participants in preventive HIV vaccine trials has been an area of continuing concern because of the need to address possible behavioral side effects (e.g., increased risk behavior because trial participants believe they may have received an active, effective vaccine) and social harms (e.g., discrimination in health care or employment because of vaccine-induced seropositivity on commercial HIV tests). Yet, the data on behavioral effects and social harms are limited and rather little detail has been provided regarding the counseling provided in current or past trials. This paper summarizes conceptual, cultural, and practical considerations in the development of a counseling program for HIV vaccine trials and provides examples from work done in the context of Phase I/II vaccine trials in Thailand.