Clinical Trials of Broadly Neutralizing Monoclonal Antibodies for Human Immunodeficiency Virus Prevention: A Review

Abstract Passive immunization with broadly neutralizing antibodies (bnAbs) is a promising approach to reduce the 1.7 million annual human immunodeficiency virus (HIV) infections globally. Early studies on bnAbs showed safety in humans, but short elimination half-lives and low potency and breadth. Since 2010, several new highly potent bnAbs have been assessed in clinical trials alone or in combination for HIV prevention. Published data indicate that these bnAbs are safe and have a half-life ranging from 15 to 71 days. Only intravenous VRC01 has advanced to an efficacy trial, with results expected in late 2020. If bnAbs are shown to be effective in preventing HIV infection, they could fast-track vaccine development as correlates of protection, and contribute as passive immunization to achieving the goal of epidemic control. The purpose of the current review is to describe the current status and provide a synopsis of the available data on bnAbs in clinical trials for HIV prevention.

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A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

Journal of General Virology ◽

10.1099/vir.0.19701-0 ◽

2004 ◽

Vol 85 (4) ◽

pp. 911-919 ◽

Cited By ~ 157

Author(s):

Matilu Mwau ◽

Inese Cebere ◽

Julian Sutton ◽

Priscilla Chikoti ◽

Nicola Winstone ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Clinical Trials ◽

Vaccinia Virus ◽

Mononuclear Cells ◽

Vaccine Development ◽

Cell Mediated Immunity ◽

Phase I Clinical Trials ◽

Modified Vaccinia Virus Ankara ◽

Immunodeficiency Virus ◽

Hiv 1

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime–boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime–MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

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Development of vaccines against the sexually transmitted infections gonorrhoea, syphilis, Chlamydia, herpes simplex virus, human immunodeficiency virus and Zika virus

Therapeutic Advances in Vaccines and Immunotherapy ◽

10.1177/2515135520923887 ◽

2020 ◽

Vol 8 ◽

pp. 251513552092388

Author(s):

Edwin David G. McIntosh

Keyword(s):

Human Immunodeficiency Virus ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Sexually Transmitted Infections ◽

Zika Virus ◽

Vaccine Development ◽

Current Status ◽

Sexually Transmitted ◽

Immunodeficiency Virus ◽

Simplex Virus

The success in preventing hepatitis B virus and human papillomavirus infections by means of vaccination paves the way for the development of other vaccines to prevent sexually transmitted infections (STIs) such as gonorrhoea, syphilis, chlamydia, herpes simplex virus, human immunodeficiency virus and Zika virus. The current status of vaccine development for these infections will be explored in this review. The general principles for success include the need for prevention of latency, persistence and repeat infections. A reduction in transmission of STIs would reduce the global burden of disease. Therapeutic activity of vaccines against STIs would be advantageous over preventative activity alone, and prevention of congenital and neonatal infections would be an added benefit. There would be an added value in the prevention of long-term consequences of STIs. It may be possible to re-purpose ‘old’ vaccines for new indications. One of the major challenges is the determination of the target populations for STI vaccination.

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Vaccines against Genital Herpes: Where Are We?

Vaccines ◽

10.3390/vaccines8030420 ◽

2020 ◽

Vol 8 (3) ◽

pp. 420

Author(s):

Hyeon Cheol Kim ◽

Heung Kyu Lee

Keyword(s):

Human Immunodeficiency Virus ◽

Genital Herpes ◽

Vaccine Development ◽

Venereal Disease ◽

Current Status ◽

Neonatal Herpes ◽

Entire Life ◽

High Burden ◽

Immunodeficiency Virus ◽

Simplex Virus

Genital herpes is a venereal disease caused by herpes simplex virus (HSV). Although HSV symptoms can be reduced with antiviral drugs, there is no cure. Moreover, because HSV infected individuals are often unaware of their infection, it is highly likely that they will transmit HSV to their sexual partner. Once infected, an individual has to live with HSV for their entire life, and HSV infection can lead to meningitis, encephalitis, and neonatal herpes as a result of vertical transmission. In addition, HSV infection increases the rates of human immunodeficiency virus (HIV) infection and transmission. Because of the high burden of genital herpes, HSV vaccines have been developed, but none have been very successful. In this review, we discuss the current status of genital herpes vaccine development.

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Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies

Journal of Virology ◽

10.1128/jvi.79.16.10108-10125.2005 ◽

2005 ◽

Vol 79 (16) ◽

pp. 10108-10125 ◽

Cited By ~ 860

Author(s):

Ming Li ◽

Feng Gao ◽

John R. Mascola ◽

Leonidas Stamatatos ◽

Victoria R. Polonis ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Standardized Assessments ◽

Subtype B ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Induction of broadly cross-reactive neutralizing antibodies is a high priority for AIDS vaccine development but one that has proven difficult to be achieved. While most immunogens generate antibodies that neutralize a subset of T-cell-line-adapted strains of human immunodeficiency virus type 1 (HIV-1), none so far have generated a potent, broadly cross-reactive response against primary isolates of the virus. Even small increments in immunogen improvement leading to increases in neutralizing antibody titers and cross-neutralizing activity would accelerate vaccine development; however, a lack of uniformity in target strains used by different investigators to assess cross-neutralization has made the comparison of vaccine-induced antibody responses difficult. Thus, there is an urgent need to establish standard panels of HIV-1 reference strains for wide distribution. To facilitate this, full-length gp160 genes were cloned from acute and early subtype B infections and characterized for use as reference reagents to assess neutralizing antibodies against clade B HIV-1. Individual gp160 clones were screened for infectivity as Env-pseudotyped viruses in a luciferase reporter gene assay in JC53-BL (TZM-bl) cells. Functional env clones were sequenced and their neutralization phenotypes characterized by using soluble CD4, monoclonal antibodies, and serum samples from infected individuals and noninfected recipients of a recombinant gp120 vaccine. Env clones from 12 R5 primary HIV-1 isolates were selected that were not unusually sensitive or resistant to neutralization and comprised a wide spectrum of genetic, antigenic, and geographic diversity. These reference reagents will facilitate proficiency testing and other validation efforts aimed at improving assay performance across laboratories and can be used for standardized assessments of vaccine-elicited neutralizing antibodies.

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Effectiveness of Voluntary Medical Male Circumcision for Human Immunodeficiency Virus Prevention in Rakai, Uganda

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1533 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gideon Loevinsohn ◽

Godfrey Kigozi ◽

Joseph Kagaayi ◽

Maria J Wawer ◽

Fred Nalugoda ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Prevention ◽

The United States ◽

Sub Saharan Africa ◽

Human Immunodeficiency Virus Prevention ◽

Voluntary Medical Male Circumcision ◽

Hiv Incidence ◽

Medical Male Circumcision ◽

Immunodeficiency Virus ◽

Hiv Acquisition

Abstract Background The efficacy of voluntary male medical circumcision (VMMC) for human immunodeficiency virus (HIV) prevention in men was demonstrated in 3 randomized trials. This led to the adoption of VMMC as an integral component of the United States President’s Emergency Plan for AIDS Relief (PEPFAR) combination HIV prevention program in sub-Saharan Africa. However, evidence on the individual-level effectiveness of VMMC programs in real-world, programmatic settings is limited. Methods A cohort of initially uncircumcised, non-Muslim, HIV-uninfected men in the Rakai Community Cohort Study in Uganda was followed between 2009 and 2016 during VMMC scale-up. Self-reported VMMC status was collected and HIV tests performed at surveys conducted every 18 months. Multivariable Poisson regression was used to estimate the incidence rate ratio (IRR) of HIV acquisition in newly circumcised vs uncircumcised men. Results A total of 3916 non-Muslim men were followed for 17 088 person-years (PY). There were 1338 newly reported VMMCs (9.8/100 PY). Over the study period, the median age of men adopting VMMC declined from 28 years (interquartile range [IQR], 21–35 years) to 22 years (IQR, 18–29 years) (P for trend < .001). HIV incidence was 0.40/100 PY (20/4992.8 PY) among newly circumcised men and 0.98/100 PY (118/12 095.1 PY) among uncircumcised men with an adjusted IRR of 0.47 (95% confidence interval, .28–.78). The effectiveness of VMMC was sustained with increasing time from surgery and was similar across age groups and calendar time. Conclusions VMMC programs are highly effective in preventing HIV acquisition in men. The observed effectiveness is consistent with efficacy in clinical trials and supports current recommendations that VMMC is a key component of programs to reduce HIV incidence.

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Improved Induction of Antibodies against Key Neutralizing Epitopes by Human Immunodeficiency Virus Type 1 gp120 DNA Prime-Protein Boost Vaccination Compared to gp120 Protein-Only Vaccination

Journal of Virology ◽

10.1128/jvi.00562-08 ◽

2008 ◽

Vol 82 (15) ◽

pp. 7369-7378 ◽

Cited By ~ 60

Author(s):

Michael Vaine ◽

Shixia Wang ◽

Emma T. Crooks ◽

Pengfei Jiang ◽

David C. Montefiori ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Gp120 Protein ◽

Protein Boost ◽

Immunodeficiency Virus ◽

Antibody Specificities ◽

Hiv 1

ABSTRACT A major challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development is to elicit potent and broadly neutralizing antibodies that are effective against primary viral isolates. Previously, we showed that DNA prime-protein boost vaccination using HIV-1 gp120 antigens was more effective in eliciting neutralizing antibodies against primary HIV-1 isolates than was a recombinant gp120 protein-only vaccination approach. In the current study, we analyzed the difference in antibody specificities in rabbit sera elicited by these two immunization regimens using peptide enzyme-linked immunosorbent assay and a competitive virus capture assay. Our results indicate that a DNA prime-protein boost regimen is more effective than a protein-alone vaccination approach in inducing antibodies that target two key neutralizing domains: the V3 loop and the CD4 binding site. In particular, positive antibodies targeting several peptides that overlap with the known CD4 binding area were detected only in DNA-primed sera. Different profiles of antibody specificities provide insight into the mechanisms behind the elicitation of better neutralizing antibodies with the DNA prime-protein boost approach, and our results support the use of this approach to further optimize Env formulations for HIV vaccine development.

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Targeted Pregnancy and Human Immunodeficiency Virus Prevention Risk-Reduction Counseling for Young Women: Lessons Learned from Biomedical Prevention Trials

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy388 ◽

2018 ◽

Vol 218 (11) ◽

pp. 1759-1766 ◽

Cited By ~ 1

Author(s):

Gita Ramjee ◽

Reshmi Dassaye ◽

Tarylee Reddy ◽

Handan Wand

Keyword(s):

Risk Factors ◽

Human Immunodeficiency Virus ◽

Hiv Prevention ◽

Pregnant Women ◽

Young Women ◽

Cox Regression ◽

Human Immunodeficiency Virus Prevention ◽

Immunodeficiency Virus ◽

Prevention Trials ◽

Hiv Acquisition

Abstract Background Women enrolled in human immunodeficiency virus (HIV) prevention efficacy trials receive counseling on prevention of HIV, sexually transmitted infections (STIs), and pregnancy during every visit. Incident pregnancy has an impact on efficacy outcomes. Incidence rates of pregnancy and HIV/STIs among women who became pregnant and associated risk factors were assessed. Methods Data from 9165 women participating in HIV prevention trials in KwaZulu-Natal, South Africa from 2002–2012 were combined. Demographic and behavioral predictors of incidence pregnancy and incidence HIV and STIs were determined using Cox regression models. Results Overall pregnancy incidence was 9.6 per 100 person-year (py) (95% confidence interval [Cl], 9.1–10.3). Human immunodeficiency virus incidence among pregnant women was 5.93 per 100 py (95% Cl, 4.73–7.44). Incidence of STIs among pregnant women for Chlamydia trachomatis, Trichomonas vaginalis, Neisseria gonorrhoeae, and Treponema pallidum (syphilis) were 10.87, 7.42, 3.92, and 1.43 per 100 py, respectively. In the adjusted analyses, we observed overlapping risk factors for HIV acquisition during pregnancy, ie, young age, not married/not cohabitating, and low parity. The risk of pregnancy and HIV acquisition is more than 3 times higher among young women (<20 years of age). Conclusions We identified overlapping risk factors for pregnancy and HIV incidence, suggesting an urgent need for appropriate, targeted, individual-centred counseling for women participating in HIV prevention trials.

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