Abstract:BackgroundA vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.Trial DesignWe conducted a randomized phase I clinical trial PedVacc… Show more
“…Given the differences between the H-2 d and HLA major histocompatibility complex molecules, only some peptides immunogenic in the BALB/c mouse are also presented by the human HLAs. Thus, peptide H is unusual in that it has four anchor residues for H-2D d ( 30 , 31 ) and displays “promiscuous” binding to four different H-2D d , H-2D p , H-2 u , and H-2 q murine determinants ( 32 ) as well as human HLA-A2 ( 33 ), although in our hands, in human volunteers ( 16 , 34 – 43 ) or HLA-A2-transgenic HHD mice (unpublished data), such responses were never detected for either the HIVA ( 20 ) or the HIVconsv ( 9 ) immunogens. No responses were detected in 23 human recipients of the HIVconsv vaccine to peptide 42 or 112, while T cells were induced to peptides 151 and 164 ( 16 ).…”
A likely requirement for a protective vaccine against human immunodeficiency virus type 1 (HIV-1)/AIDS is, in addition to eliciting antibody responses, induction of effective T cells. To tackle HIV-1 diversity by T-cell vaccines, we designed an immunogen, HIVconsv, derived from the most functionally conserved regions of the HIV-1 proteome and demonstrated its high immunogenicity in humans and rhesus macaques when delivered by regimens combining plasmid DNA, nonreplicating simian (chimpanzee) adenovirus ChAdV-63, and nonreplicating modified vaccinia virus Ankara (MVA) as vectors. Here, we aimed to increase the decision power for iterative improvements of this vaccine strategy in the BALB/c mouse model. First, we found that prolonging the period after the ChAdV63.HIVconsv prime up to 6 weeks increased the frequencies of HIV-1-specific, gamma interferon (IFN-γ)-producing T cells induced by the MVA.HIVconsv boost. Induction of strong responses allowed us to map comprehensively the H-2d-restricted T-cell responses to these regions and identified 8 HIVconsv peptides, of which three did not contain a previously described epitope and were therefore considered novel. Induced effector T cells were oligofunctional and lysed sensitized targets in vitro. Our study therefore provides additional tools for studying and optimizing vaccine regimens in this commonly used small animal model, which will in turn guide vaccine improvements in more expensive nonhuman primate and human clinical trials.
“…Given the differences between the H-2 d and HLA major histocompatibility complex molecules, only some peptides immunogenic in the BALB/c mouse are also presented by the human HLAs. Thus, peptide H is unusual in that it has four anchor residues for H-2D d ( 30 , 31 ) and displays “promiscuous” binding to four different H-2D d , H-2D p , H-2 u , and H-2 q murine determinants ( 32 ) as well as human HLA-A2 ( 33 ), although in our hands, in human volunteers ( 16 , 34 – 43 ) or HLA-A2-transgenic HHD mice (unpublished data), such responses were never detected for either the HIVA ( 20 ) or the HIVconsv ( 9 ) immunogens. No responses were detected in 23 human recipients of the HIVconsv vaccine to peptide 42 or 112, while T cells were induced to peptides 151 and 164 ( 16 ).…”
A likely requirement for a protective vaccine against human immunodeficiency virus type 1 (HIV-1)/AIDS is, in addition to eliciting antibody responses, induction of effective T cells. To tackle HIV-1 diversity by T-cell vaccines, we designed an immunogen, HIVconsv, derived from the most functionally conserved regions of the HIV-1 proteome and demonstrated its high immunogenicity in humans and rhesus macaques when delivered by regimens combining plasmid DNA, nonreplicating simian (chimpanzee) adenovirus ChAdV-63, and nonreplicating modified vaccinia virus Ankara (MVA) as vectors. Here, we aimed to increase the decision power for iterative improvements of this vaccine strategy in the BALB/c mouse model. First, we found that prolonging the period after the ChAdV63.HIVconsv prime up to 6 weeks increased the frequencies of HIV-1-specific, gamma interferon (IFN-γ)-producing T cells induced by the MVA.HIVconsv boost. Induction of strong responses allowed us to map comprehensively the H-2d-restricted T-cell responses to these regions and identified 8 HIVconsv peptides, of which three did not contain a previously described epitope and were therefore considered novel. Induced effector T cells were oligofunctional and lysed sensitized targets in vitro. Our study therefore provides additional tools for studying and optimizing vaccine regimens in this commonly used small animal model, which will in turn guide vaccine improvements in more expensive nonhuman primate and human clinical trials.
“…HIV-1 testing was performed using HIV-1 DNA PCR at birth, 6, 10, 14 and 20 weeks; HIV-1 viral load at 19, 28, 36 and 48 weeks and HIV-ELISA at 48 weeks. Peripheral blood mononuclear cells (PBMC) were isolated and used for interferon (IFN)-γ ELISPOT assays or frozen [23] .…”
Section: Methodsmentioning
confidence: 99%
“…Fresh ex vivo and cultured IFN-γ ELISPOT assays were carried out as previously described [23] . An assay failed quality control if the mean background was >20 spot-forming units (SFU)/well (>100 SFU/10 6 PBMC) or mean phytohemagglutinine response was <30 SFU/well (<150 SFU/10 6 PBMC).…”
Section: Methodsmentioning
confidence: 99%
“…The tested ALVAC and protein vaccines caused no increase in serious adverse events (SAE) and elicited promising immune responses similar to those observed in adults. We recently reported that the PedVacc 001 trial had excellent safety and marginal immunogenicity among 20-week-old Gambian infants born to HIV-1-negative mothers [23] . Here, we report on the administration of MVA.HIVA to infants born to HIV-1-positive mothers in Kenya (PedVacc 002) with the primary aim to assess its safety.…”
HighlightsMVA.HIVA vaccine was tested for the first time in HIV-1-exposed infants in Africa.PedVacc 002 had 99% retention of infants over 48 weeks of follow-up.MVA.HIVA was safe, but not sufficiently immunogenic.MVA.HVA did not interfere with routine childhood vaccines except for induction of HBV antibodies.MVA is well suited as a vaccine vector for infants under 1 year of age.
“…No severe adverse events occurred during the trial, and the vaccine did not interfere with antibody induction to the standard childhood vaccines. However, only 9% of vaccinated infants demonstrated an HIV-1-specific T cell response [65]. The most promising vaccine study so far, a trial of ALVAC-HIV vCP 1521 among adults in Thailand that incorporated boosting with 2 recombinant envelope proteins, found that the vaccine had 31% efficacy (95% CI: 1.1–51.1%; P = .04) [66].…”
Summary
The prevention of mother-to-child transmission (PMTCT) of HIV is one of the great public health successes of the past 20 years. Much concerted research efforts and dedicated work have led to the achievement of very low rates of PMTCT of HIV in settings that can implement optimal prophylaxis. Though several implementation challenges remain, global elimination of pediatric HIV infection seems now more than ever to be an attainable goal. Often overlooked, the role of prophylaxis of the newborn is nevertheless a very important component of PMTCT. In this paper, we focus on the role of neonatal and infant prophylaxis, discuss mechanisms of protection, and present the clinical trial-generated evidence that led to the current recommendations for preventing infections in breastfed and nonbreastfed infants. PMTCT of HIV should not end at birth; a continuum of care extending postpartum and postnatally is required to minimize the risk of new pediatric HIV infections.
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