Antibody responses to prime–boost vaccination with an HIV-1 gp145 envelope protein and chimpanzee adenovirus vectors expressing HIV-1 gp140

ABSTRACTWe evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4+and CD8+T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model.IMPORTANCEHSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.

Download Full-text

Boosting of HIV-1 Neutralizing Antibody Responses by a Distally Related Retroviral Envelope Protein

The Journal of Immunology ◽

10.4049/jimmunol.1301898 ◽

2014 ◽

Vol 192 (12) ◽

pp. 5802-5812 ◽

Cited By ~ 4

Author(s):

Hannes Uchtenhagen ◽

Torben Schiffner ◽

Emma Bowles ◽

Leo Heyndrickx ◽

Celia LaBranche ◽

...

Keyword(s):

Envelope Protein ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Hiv 1

Download Full-text

A Clinical Trial to Evaluate the Safety and Immunogenicity of Recombinant HIV-1 Envelope Protein BG505 SOSIP.GT1.1 gp140 Vaccine, Adjuvanted in Healthy, HIV-uninfected Adults

Case Medical Research ◽

10.31525/ct1-nct04224701 ◽

2020 ◽

Author(s):

Keyword(s):

Clinical Trial ◽

Envelope Protein ◽

Hiv 1

Download Full-text

Faculty Opinions recommendation of A novel strategy for inducing enhanced mucosal HIV-1 antibody responses in an anti-inflammatory environment.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.9556960.10214059 ◽

2011 ◽

Author(s):

Susana Asin ◽

Christiane Rollenhagen

Keyword(s):

Antibody Responses ◽

Anti Inflammatory ◽

Novel Strategy ◽

Hiv 1

Download Full-text

Immunogenicity of HIV-1-Based Virus-Like Particles with Increased Incorporation and Stability of Membrane-Bound Env

Vaccines ◽

10.3390/vaccines9030239 ◽

2021 ◽

Vol 9 (3) ◽

pp. 239

Author(s):

Christopher A. Gonelli ◽

Hannah A. D. King ◽

Charlene Mackenzie ◽

Secondo Sonza ◽

Rob J. Center ◽

...

Keyword(s):

Neutralizing Antibody ◽

Antibody Responses ◽

Neutralization Activity ◽

Virus Like Particles ◽

Antibody Isotypes ◽

Immunodeficiency Virus ◽

Proline Substitution ◽

Membrane Bound ◽

Antibody Epitopes ◽

Hiv 1

An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice. The incorporation of Env into mVLPs was increased by replacing the Env transmembrane and cytoplasmic tail domains with those of influenza haemagglutinin (HA-TMCT). Furthermore, Env was stabilized on the VLP surface by introducing an interchain disulfide and proline substitution (SOSIP) mutations typically employed to stabilize soluble Env trimers. The resulting mVLPs efficiently presented neutralizing antibody epitopes while minimizing exposure of non-neutralizing antibody sites. Vaccination of mice with mVLPs elicited a broader range of Env-specific antibody isotypes than Env presented on immature VLPs or extracellular vesicles. The mVLPs bearing HA-TMCT-modified Env consistently induced anti-Env antibody responses that mediated modest neutralization activity. These mVLPs are potentially useful immunogens for eliciting neutralizing antibody responses that target native Env epitopes on infectious HIV-1 virions.

Download Full-text

Continuous HIV-1 Escape from Autologous Neutralization and Development of Cross-Reactive Antibody Responses Characterizes Slow Disease Progression of Children

Vaccines ◽

10.3390/vaccines9030260 ◽

2021 ◽

Vol 9 (3) ◽

pp. 260

Author(s):

Stefania Dispinseri ◽

Mariangela Cavarelli ◽

Monica Tolazzi ◽

Anna Maria Plebani ◽

Marianne Jansson ◽

...

Keyword(s):

Disease Progression ◽

Antibody Responses ◽

Viral Escape ◽

Target Cells ◽

Transmitted Virus ◽

Slow Progressors ◽

Vaccine Antigens ◽

Kinetics Of ◽

Hiv 1

The antibodies with different effector functions evoked by Human Immunodeficiency Virus type 1 (HIV-1) transmitted from mother to child, and their role in the pathogenesis of infected children remain unresolved. So, too, the kinetics and breadth of these responses remain to be clearly defined, compared to those developing in adults. Here, we studied the kinetics of the autologous and heterologous neutralizing antibody (Nab) responses, in addition to antibody-dependent cellular cytotoxicity (ADCC), in HIV-1 infected children with different disease progression rates followed from close after birth and five years on. Autologous and heterologous neutralization were determined by Peripheral blood mononuclear cells (PBMC)- and TZMbl-based assays, and ADCC was assessed with the GranToxiLux assay. The reactivity to an immunodominant HIV-1 gp41 epitope, and childhood vaccine antigens, was assessed by ELISA. Newborns displayed antibodies directed towards the HIV-1 gp41 epitope. However, antibodies neutralizing the transmitted virus were undetectable. Nabs directed against the transmitted virus developed usually within 12 months of age in children with slow progression, but rarely in rapid progressors. Thereafter, autologous Nabs persisted throughout the follow-up of the slow progressors and induced a continuous emergence of escape variants. Heterologous cross-Nabs were detected within two years, but their subsequent increase in potency and breadth was mainly a trait of slow progressors. Analogously, titers of antibodies mediating ADCC to gp120 BaL pulsed target cells increased in slow progressors during follow-up. The kinetics of antibody responses to the immunodominant viral antigen and the vaccine antigens were sustained and independent of disease progression. Persistent autologous Nabs triggering viral escape and an increase in the breadth and potency of cross-Nabs are exclusive to HIV-1 infected slowly progressing children.

Download Full-text

A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

Scientific Reports ◽

10.1038/s41598-021-84116-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jean-François Bruxelle ◽

Tess Kirilenko ◽

Nino Trattnig ◽

Yiqiu Yang ◽

Matteo Cattin ◽

...

Keyword(s):

Transgenic Mice ◽

Envelope Protein ◽

Protein Sequence ◽

Neutralizing Antibodies ◽

Human Antibody ◽

Broadly Neutralizing Antibodies ◽

Specific Antibodies ◽

Strong Binding ◽

Hiv Envelope ◽

Hiv 1

AbstractThe occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by inferred germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

Download Full-text