Safety, Tolerability, and Pharmacokinetics of the Broadly Neutralizing Human Immunodeficiency Virus (HIV)-1 Monoclonal Antibody VRC01 in HIV-Exposed Newborn Infants

Cunningham, Coleen K.; McFarland, Elizabeth J.; Morrison, Randall L.; Capparelli, Edmund V.; Safrit, Jeffrey T.; Mofenson, Lynne; Mathieson, Bonnie J.; Valentine, Megan; Perlowski, Charlotte; Smith, Betsy; Hazra, Rohan; Purdue, Lynette; Muresan, Petronella; Harding, Paul A.; Mbengeranwa, Tapiwa; Robinson, Lucy; Wiznia, Andrew; Theron, Gerhard; Lin, Bob C.; Bailer, Robert T.; Mascola, John R.; Graham, Barney S.; Team, Impaact P s Protocol

doi:10.1093/infdis/jiz532

Cited by 48 publications

(42 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar in intent and yet different in approach to bNAbs, engineered antibody-like entry inhibitor molecules (eCD4-Ig) that simultaneously emulate both the target CD4 receptor and a coreceptor, CXCR4 or CCR5, have demonstrated a capacity for high neutralization breadth and a lower potential for viral escape than a single bNAb (35). In contrast to the concerns associated with the administration of single bNAb as a maternal intervention, a recent phase I study has demonstrated the safety, tolerability, and pharmacokinetics of passive administration of VRC01-LS bNAb in HIV-exposed infants as adjunctive therapy to ART to further reduce postnatal transmission via breastfeeding (36). Thus, while development of a safe and highly effective maternal HIV vaccine remains elusive, passive immunization strategies may be used to complement existing maternal and infant ART regimens.…”

Section: Discussionmentioning

confidence: 99%

Induction of Neutralizing Responses against Autologous Virus in Maternal HIV Vaccine Trials

Hompe

Mangold

Kumar

et al. 2020

mSphere

View full text Add to dashboard Cite

A maternal vaccine capable of boosting neutralizing antibody (NAb) responses directed against circulating viruses in HIV-infected pregnant women could effectively decrease mother-to-child transmission of HIV. However, it is not known if an HIV envelope (Env) vaccine administered to infected pregnant women could enhance autologous virus neutralization and thereby reduce this risk of vertical HIV transmission. Here, we assessed autologous virus NAb responses in maternal plasma samples obtained from AIDS Vaccine Evaluation Group (AVEG) protocols 104 and 102, representing historical phase I safety and immunogenicity trials of recombinant HIV Env subunit vaccines administered to HIV-infected pregnant women (ClinicalTrials registration no. NCT00001041). Maternal HIV Env-specific plasma binding and neutralizing antibody responses were characterized before and after vaccination in 15 AVEG 104 (n = 10 vaccine recipients, n = 5 placebo recipients) and 2 AVEG 102 (n = 1 vaccine recipient, n = 1 placebo recipient) participants. Single-genome amplification (SGA) was used to obtain HIV env gene sequences of autologous maternal viruses for pseudovirus production and neutralization sensitivity testing in pre- and postvaccination plasma of HIV-infected pregnant vaccine recipients (n = 6 gp120, n = 1 gp160) and placebo recipients (n = 3). We detected an increase in Env subunit MN gp120-specific IgG binding in the group of vaccine recipients between the first immunization visit and the last visit at delivery (P = 0.027, 2-sided Wilcoxon test). While no difference was observed in the levels of autologous virus neutralization potency between groups, in both groups maternal plasma collected at delivery more effectively neutralized autologous viruses from early pregnancy than late pregnancy. Immunization strategies capable of further enhancing these autologous virus NAb responses in pregnant women will be important to block vertical transmission of HIV. IMPORTANCE Maternal antiretroviral therapy (ART) has effectively reduced but not eliminated the burden of mother-to-child transmission of HIV across the globe, as an estimated 160,000 children were newly infected with HIV in 2018. Thus, additional preventive strategies beyond ART will be required to close the remaining gap and end the pediatric HIV epidemic. A maternal active immunization strategy that synergizes with maternal ART could further reduce infant HIV infections. In this study, we found that two historic HIV Env vaccines did not enhance the ability of HIV-infected pregnant women to neutralize autologous viruses. Therefore, next-generation maternal HIV vaccine candidates must employ alternate approaches to achieve potent neutralizing antibody and perhaps nonneutralizing antibody responses to effectively impede vertical virus transmission. Moreover, these approaches must reflect the broad diversity of HIV strains and widespread availability of ART worldwide.

show abstract

Section: Discussionmentioning

confidence: 99%

Induction of Neutralizing Responses against Autologous Virus in Maternal HIV Vaccine Trials

Hompe

Mangold

Kumar

et al. 2020

mSphere

View full text Add to dashboard Cite

show abstract

“…Phase I studies showed VRC01 to be safe and well tolerated without dose-associated toxicity or serious adverse effects in healthy adults and HIV-exposed infants [6,25]. Its long-term clinical and functional activities have also been examined in healthy humans.…”

Section: Efficacy Of Next-generation Bnabs In Clinical Trialsmentioning

confidence: 99%

Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities

Liu

Cao

Sun

et al. 2020

Emerging Microbes & Infections

View full text Add to dashboard Cite

Combination antiretroviral therapy (cART) is effective but not curative, and no successful vaccine is currently available for human immunodeficiency virus-1 (HIV-1). Broadly neutralizing antibodies (bNAbs) provide a new approach to HIV-1 prevention and treatment, and these promising candidates advancing into clinical trials have shown certain efficacies in infected individuals. In addition, bNAbs have the potential to kill HIV-1-infected cells and to affect the course of HIV-1 infection by directly engaging host immunity. Nonetheless, challenges accompany the use of bNAbs, including transient suppression of viraemia, frequent emergence of resistant viruses in rebound viraemia, suboptimal efficacy in virus cell-tocell transmission, and unclear effects on the cell-associated HIV-1 reservoir. In this review, we discuss opportunities and potential strategies to address current challenges to promote the future use of immunotherapy regimens.

show abstract

“…VRC01, VRC01LS and VRC07-523LS were administered subcutaneously to HIV-exposed infants. VRC01 demonstrated a good safety profile when administered as either a single dose or in multiple doses [55].…”

Section: Subcutaneous Injection Of Antibodymentioning

confidence: 99%

Review of preventative HIV vaccine clinical trials in South Africa

et al. 2020

View full text Add to dashboard Cite

New HIV infections continue relentlessly in southern Africa, demonstrating the need for a vaccine to prevent HIV subtype C. In South Africa, the country with the highest number of new infections annually, HIV vaccine research has been ongoing since 2003 with collaborative public-private-philanthropic partnerships. So far, 21 clinical trials have been conducted in South Africa, investigating seven viral vectors, three DNA plasmids, four envelope proteins, five adjuvants and three monoclonal antibodies. Active vaccine candidates have spanned subtypes A, B, C, E and multi-subtype mosaic sequences. All were well tolerated. Four concepts were investigated for efficacy: rAd5-gag/pol/nef showed increased HIV acquisition in males, subtype C ALVAC/gp120/MF59 showed no preventative efficacy, and the trials for the VRC01 monoclonal antibody and Ad26.Mos4.HIV/subtype C gp140/ aluminum phosphate are ongoing. Future trials are planned with DNA/viral vector plus protein combinations in concert with pre-exposure prophylaxis, and sequential immunization studies with transmitted/founder HIV envelope to induce broadly neutralizing antibodies. Finally, passive immunization trials are underway to build on the experience with VRC01, including single and combination antibody trials with an antibody derived from a subtype-C-infected South African donor. Future consideration should be given to the evaluation of novel strategies, for example, inactivated-whole-virus vaccines.

show abstract

Safety, Tolerability, and Pharmacokinetics of the Broadly Neutralizing Human Immunodeficiency Virus (HIV)-1 Monoclonal Antibody VRC01 in HIV-Exposed Newborn Infants

Cited by 48 publications

References 28 publications

Induction of Neutralizing Responses against Autologous Virus in Maternal HIV Vaccine Trials

Induction of Neutralizing Responses against Autologous Virus in Maternal HIV Vaccine Trials

Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities

Review of preventative HIV vaccine clinical trials in South Africa

Contact Info

Product

Resources

About