Inclusion of a CRF01_AE HIV envelope protein boost with a DNA/MVA prime-boost vaccine: Impact on humoral and cellular immunogenicity and viral load reduction after SHIV-E challenge.

The current study assessed the immunogenicity and protective efficacy of various prime-boost vaccine regimens in rhesus macaques using combinations of recombinant DNA (rDNA), recombinant MVA (rMVA), and subunit gp140 protein. The rDNA and rMVA vectors were constructed to express Env from HIV-1 subtype CRF01_AE and Gag-Pol from CRF01_AE or SIVmac 239. One of the rMVAs, MVA/CMDR, has been recently tested in humans. Immunizations were administered at months 0 and 1 (prime) and months 3 and 6 (boost). After priming, HIV env-specific serum IgG was detected in monkeys receiving gp140 alone or rMVA but not in those receiving rDNA. Titers were enhanced in these groups after boosting either with gp140 alone or with rMVA plus gp140. The groups that received the rDNA prime developed env-specific IgG after boosting with rMVA with or without gp140. HIV Env-specific serum IgG binding antibodies were elicited more frequently and of higher titer, and breadth of neutralizing antibodies was increased with the inclusion of the subunit Env boost. T cell responses were measured by tetramer binding to Gag p11c in Mamu-A*01 macaques, and by IFN-γ ELISPOT assay to SIV-Gag. T cell responses were induced after vaccination with the highest responses seen in macaques immunized with rDNA and rMVA. Macaques were challenged intravenously with a novel SHIV-E virus (SIVmac239 Gag-Pol with an HIV-1 subtype E-Env CAR402). Post challenge with SHIV-E, antibody titers were boosted in all groups and peaked at 4 weeks. Robust T cell responses were seen in all groups post challenge and in macaques immunized with rDNA and rMVA a clear boosting of responses was seen. A greater than two-log drop in RNA copies/ml at peak viremia and earlier set point was achieved in macaques primed with rDNA, and boosted with rMVA/SHIV-AE plus gp140. Post challenge viremia in macaques immunized with other regimens was not significantly different to that of controls. These results demonstrate that a gp140 subunit and inclusion of SIV Gag-Pol may be critical for control of SHIV post challenge.

Cox JH ，Ferrari MG ，Earl P ，Lane JR ，Jagodzinski LL ，Polonis VR ，Kuta EG ，Boyer JD ，Ratto-Kim S ，Eller LA ，Pham DT ，Hart L ，Montefiori D ，Ferrari G ，Parrish S ，Weiner DB ，Moss B ，Kim JH ，Birx D ，VanCott TC ... -  《-》

Comparison of vaccine strategies using recombinant env-gag-pol MVA with or without an oligomeric Env protein boost in the SHIV rhesus macaque model.

Earl PL ，Wyatt LS ，Montefiori DC ，Bilska M ，Woodward R ，Markham PD ，Malley JD ，Vogel TU ，Allen TM ，Watkins DI ，Miller N ，Moss B ... -  《VIROLOGY》

Multiprotein HIV type 1 clade B DNA/MVA vaccine: construction, safety, and immunogenicity in Macaques.

Smith JM ，Amara RR ，McClure HM ，Patel M ，Sharma S ，Yi H ，Chennareddi L ，Herndon JG ，Butera ST ，Heneine W ，Ellenberger DL ，Parekh B ，Earl PL ，Wyatt LS ，Moss B ，Robinson HL ... -  《AIDS RESEARCH AND HUMAN RETROVIRUSES》

Optimizing the immunogenicity of HIV prime-boost DNA-MVA-rgp140/GLA vaccines in a phase II randomized factorial trial design.

Viegas EO ，Kroidl A ，Munseri PJ ，Missanga M ，Nilsson C ，Tembe N ，Bauer A ，Joachim A ，Joseph S ，Mann P ，Geldmacher C ，Fleck S ，Stöhr W ，Scarlatti G ，Aboud S ，Bakari M ，Maboko L ，Hoelscher M ，Wahren B ，Robb ML ，Weber J ，McCormack S ，Biberfeld G ，Jani IV ，Sandström E ，Lyamuya E ，TaMoVac study group ... -  《PLoS One》

Human Immunodeficiency Virus C.1086 Envelope gp140 Protein Boosts following DNA/Modified Vaccinia Virus Ankara Vaccination Fail To Enhance Heterologous Anti-V1V2 Antibody Response and Protection against Clade C Simian-Human Immunodeficiency Virus Challeng

The RV144 human immunodeficiency virus type 1 (HIV-1) vaccine trial showed a strong association between anti-gp70 V1V2 scaffold (V1V2) and anti-V2 hot spot peptide (V2 HS) antibody responses and reduced risk of HIV infection. Accordingly, a primary goal for HIV vaccines is to enhance the magnitude and breadth of V1V2 and V2 HS antibody responses in addition to neutralizing antibodies. Here, we tested the immunogenicity and efficacy of HIV-1 C.1086 gp140 boosts administered sequentially after priming with CD40L-adjuvanted DNA/simian-human immunodeficiency virus (SHIV) and boosting with modified vaccinia virus Ankara (MVA)-SHIV vaccines in rhesus macaques. The DNA/MVA vaccination induced robust vaccine-specific CD4 and CD8 T cell responses with a polyfunctional profile. Two gp140 booster immunizations induced very high levels (∼2 mg/ml) of gp140 binding antibodies in serum, with strong reactivity directed against the homologous (C.1086) V1V2, V2 HS, V3, and gp41 immunodominant (ID) proteins. However, the vaccine-induced antibody showed 10-fold (peak) and 32-fold (prechallenge) weaker binding to the challenge virus (SHIV1157ipd3N4) V1V2 and failed to bind to the challenge virus V2 HS due to a single amino acid change. Point mutations in the immunogen V2 HS to match the V2 HS in the challenge virus significantly diminished the binding of vaccine-elicited antibodies to membrane-anchored gp160. Both vaccines failed to protect from infection following repeated SHIV1157ipd3N4 intrarectal challenges. However, only the protein-boosted animals showed enhanced viral control. These results demonstrate that C.1086 gp140 protein immunizations administered following DNA/MVA vaccination do not significantly boost heterologous V1V2 and V2 HS responses and fail to enhance protection against heterologous SHIV challenge.IMPORTANCE HIV, the virus that causes AIDS, is responsible for millions of infections and deaths annually. Despite intense research for the past 25 years, there remains no safe and effective vaccine available. The significance of this work is in identifying the pros and cons of adding a protein boost to an already well-established DNA/MVA HIV vaccine that is currently being tested in the clinic. Characterizing the effects of the protein boost can allow researchers going forward to design vaccines that generate responses that will be more effective against HIV. Our results in rhesus macaques show that boosting with a specific HIV envelope protein does not significantly boost antibody responses that were identified as immune correlates of protection in a moderately successful RV144 HIV vaccine trial in humans and highlight the need for the development of improved HIV envelope immunogens.

Styles TM ，Gangadhara S ，Reddy PBJ ，Hicks S ，LaBranche CC ，Montefiori DC ，Derdeyn CA ，Kozlowski PA ，Velu V ，Amara RR ... -  《-》