Recombinant varicella vaccines induce neutralizing antibodies and cellular immune responses to SIV and reduce viral loads in immunized rhesus macaques

ABSTRACT In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virusmac251. Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIVmac251 challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A∗01 animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8+ T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites.

Download Full-text

Induction of Neutralizing Antibodies and Gag-Specific Cellular Immune Responses to an R5 Primary Isolate of Human Immunodeficiency Virus Type 1 in Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.75.13.5879-5890.2001 ◽

2001 ◽

Vol 75 (13) ◽

pp. 5879-5890 ◽

Cited By ~ 52

Author(s):

David C. Montefiori ◽

Jeffrey T. Safrit ◽

Shari L. Lydy ◽

Ashley P. Barry ◽

Miroslawa Bilska ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Ifn Γ ◽

Cellular Immune ◽

Hiv 1

ABSTRACT The ability to generate antibodies that cross-neutralize diverse primary isolates is an important goal for human immunodeficiency virus type 1 (HIV-1) vaccine development. Most of the candidate HIV-1 vaccines tested in humans and nonhuman primates have failed in this regard. Past efforts have focused almost entirely on the envelope glycoproteins of a small number of T-cell line-adapted strains of the virus as immunogens. Here we assessed the immunogenicity of noninfectious virus-like particles (VLP) consisting of Gag, Pro (protease), and Env from R5 primary isolate HIV-1Bx08. Immunogens were delivered to rhesus macaques in the form of either purified VLP, recombinant DNA and canarypox (ALVAC) vectors engineered to express VLP, or a combination of these products. Seroconversion to Gag and Pro was detected in all of the immunized animals. Antibodies that could neutralize HIV-1Bx08 were detected in animals that received (i) coinoculations with DNABx08 and VLPBx08, (ii) DNABx08 followed by ALVACBx08 boosting, and (iii) VLPBx08 alone. The neutralizing antibodies were highly strain specific despite the fact that they did not appear to be directed to linear epitopes in the V3 loop. Virus-specific cellular immune responses also were generated, as judged by the presence of Gag-specific gamma interferon (IFN-γ)-producing cells. These cellular immune responses required the inclusion of DNABx08 in the immunization modality, since few or no IFN-γ-producing cells were detected in animals that received either VLPBx08 or ALVACBx08 alone. The results demonstrate the feasibility of generating neutralizing antibodies and cellular immune responses that target an R5 primary HIV-1 isolate by vaccination in primates.

Download Full-text

SARS-CoV-2 infection protects against rechallenge in rhesus macaques

Science ◽

10.1126/science.abc4776 ◽

2020 ◽

Vol 369 (6505) ◽

pp. 812-817 ◽

Cited By ~ 199

Author(s):

Abishek Chandrashekar ◽

Jinyan Liu ◽

Amanda J. Martinot ◽

Katherine McMahan ◽

Noe B. Mercado ◽

...

Keyword(s):

Immune Responses ◽

Protective Immunity ◽

Nonhuman Primates ◽

Rhesus Macaques ◽

Viral Loads ◽

Macaque Model ◽

Cellular Immune Responses ◽

Immunologic Control ◽

Cellular Immune ◽

Public Health Strategies

An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.

Download Full-text

Vaccine-Induced Cellular Responses Control Simian Immunodeficiency Virus Replication after Heterologous Challenge

Journal of Virology ◽

10.1128/jvi.00272-09 ◽

2009 ◽

Vol 83 (13) ◽

pp. 6508-6521 ◽

Cited By ~ 103

Author(s):

Nancy A. Wilson ◽

Brandon F. Keele ◽

Jason S. Reed ◽

Shari M. Piaskowski ◽

Caitlin E. MacNair ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Chronic Phase ◽

Structural Features ◽

Viral Loads ◽

Log Reduction ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Cellular Immune

ABSTRACT All human immunodeficiency virus (HIV) vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T-cell responses against 11 to 34 epitopes. We challenged the vaccinees and eight naïve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both the peak (1.9-log reduction; P < 0.03) and at the set point (2.6-log reduction; P < 0.006) than those in control naïve animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 viral RNA (vRNA) copy eq/ml and to less than 100 vRNA copy eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T-cell-based vaccines may have greater potential than previously appreciated.

Download Full-text

Cytomegalovirus Vaccine Strain Towne-Derived Dense Bodies Induce Broad Cellular Immune Responses and Neutralizing Antibodies That Prevent Infection of Fibroblasts and Epithelial Cells

Journal of Virology ◽

10.1128/jvi.01554-13 ◽

2013 ◽

Vol 87 (20) ◽

pp. 11107-11120 ◽

Cited By ~ 38

Author(s):

C. Cayatte ◽

K. Schneider-Ohrum ◽

Z. Wang ◽

A. Irrinki ◽

N. Nguyen ◽

...

Keyword(s):

Epithelial Cells ◽

Immune Responses ◽

Vaccine Strain ◽

Neutralizing Antibodies ◽

Cellular Immune Responses ◽

Dense Bodies ◽

Cellular Immune ◽

Cytomegalovirus Vaccine

Download Full-text

Simultaneous Administration of Recombinant Measles Viruses Expressing Respiratory Syncytial Virus Fusion (F) and Nucleo (N) Proteins Induced Humoral and Cellular Immune Responses in Cotton Rats

Vaccines ◽

10.3390/vaccines7010027 ◽

2019 ◽

Vol 7 (1) ◽

pp. 27 ◽

Cited By ~ 2

Author(s):

Yoshiaki Yamaji ◽

Akihito Sawada ◽

Yosuke Yasui ◽

Takashi Ito ◽

Tetsuo Nakayama

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Simultaneous Administration ◽

Cellular Immune Responses ◽

Immunization Group ◽

Cotton Rats ◽

Ifn Γ ◽

Syncytial Virus ◽

Cellular Immune

We previously reported that recombinant measles virus expressing the respiratory syncytial virus (RSV) fusion protein (F), MVAIK/RSV/F, induced neutralizing antibodies against RSV, and those expressing RSV-NP (MVAIK/RSV/NP) and M2-1 (MVAIK/RSV/M2-1) induced RSV-specific CD8+/IFN-γ+ cells, but not neutralizing antibodies. In the present study, MVAIK/RSV/F and MVAIK/RSV/NP were simultaneously administered to cotton rats and immune responses and protective effects were compared with MVAIK/RSV/F alone. Sufficient neutralizing antibodies against RSV and RSV-specific CD8+/IFN-γ+ cells were observed after re-immunization with simultaneous administration. After the RSV challenge, CD8+/IFN-γ+ increased in spleen cells obtained from the simultaneous immunization group in response to F and NP peptides. Higher numbers of CD8+/IFN-γ+ and CD4+/IFN-γ+ cells were detected in lung tissues from the simultaneous immunization group after the RSV challenge. No detectable RSV was recovered from lung homogenates in the immunized groups. Mild inflammatory reactions with the thickening of broncho-epithelial cells and the infiltration of inflammatory cells were observed in lung tissues obtained from cotton rats immunized with MVAIK/RSV/F alone after the RSV challenge. No inflammatory responses were observed after the RSV challenge in the simultaneous immunization groups. The present results indicate that combined administration with MVAIK/RSV/F and MVAIK/RSV/NP induces humoral and cellular immune responses and shows effective protection against RSV, suggesting the importance of cellular immunity.

Download Full-text

Strong HCV NS3- and NS4A-specific cellular immune responses induced in mice and Rhesus macaques by a novel HCV genotype 1a/1b consensus DNA vaccine

Vaccine ◽

10.1016/j.vaccine.2008.07.052 ◽

2008 ◽

Vol 26 (49) ◽

pp. 6225-6231 ◽

Cited By ~ 28

Author(s):

Krystle A. Lang ◽

Jian Yan ◽

Ruxandra Draghia-Akli ◽

Amir Khan ◽

David B. Weiner

Keyword(s):

Immune Responses ◽

Dna Vaccine ◽

Rhesus Macaques ◽

Hcv Genotype ◽

Cellular Immune Responses ◽

Genotype 1A ◽

Cellular Immune

Download Full-text

Safety and Immunogenicity of Heterologous and Homologous 2-Dose Regimens of Adenovirus Serotype 26– and Modified Vaccinia Ankara–Vectored Ebola Vaccines: A Randomized, Controlled Phase 1 Study

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa586 ◽

2020 ◽

Cited By ~ 1

Author(s):

Neil Goldstein ◽

Viki Bockstal ◽

Stephan Bart ◽

Kerstin Luhn ◽

Cynthia Robinson ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Ebola Virus ◽

Phase 1 ◽

Booster Vaccination ◽

Controlled Study ◽

Adenovirus Serotype ◽

Cellular Immune Responses ◽

High Doses ◽

Cellular Immune

Abstract Background This phase 1 placebo-controlled study assessed the safety and immunogenicity of 2-dose regimens of Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and MVA-BN-Filo (modified vaccinia Ankara [MVA]) vaccines with booster vaccination at day 360. Methods Healthy US adults (N = 164) randomized into 10 groups received saline placebo or standard or high doses of Ad26 or MVA in 2-dose regimens at 7-, 14-, 28-, or 56-day intervals; 8 groups received booster Ad26 or MVA vaccinations on day 360. Participants reported solicited and unsolicited reactogenicity; we measured immunoglobulin G binding, neutralizing antibodies and cellular immune responses to Ebola virus glycoprotein. Results All regimens were well tolerated with no serious vaccine-related adverse events. Heterologous (Ad26,MVA [dose 1, dose 2] or MVA,Ad26) and homologous (Ad26,Ad26) regimens induced humoral and cellular immune responses 21 days after dose 2; responses were higher after heterologous regimens. Booster vaccination elicited anamnestic responses in all participants. Conclusions Both heterologous and homologous Ad26,MVA Ebola vaccine regimens are well tolerated in healthy adults, regardless of interval or dose level. Heterologous 2-dose Ad26,MVA regimens containing an Ebola virus insert induce strong, durable humoral and cellular immune responses. Immunological memory was rapidly recalled by booster vaccination, suggesting that Ad26 booster doses could be considered for individuals at risk of Ebola infection, who previously received the 2-dose regimen.

Download Full-text

Human Immunodeficiency Virus Type 1-Hepatitis C Virus Coinfection: Intraindividual Comparison of Cellular Immune Responses against Two Persistent Viruses

Journal of Virology ◽

10.1128/jvi.76.6.2817-2826.2002 ◽

2002 ◽

Vol 76 (6) ◽

pp. 2817-2826 ◽

Cited By ~ 69

Author(s):

Georg M. Lauer ◽

Tam N. Nguyen ◽

Cheryl L. Day ◽

Gregory K. Robbins ◽

Theresa Flynn ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

T Lymphocyte ◽

Viral Loads ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Cellular Immune ◽

Lymphocyte Responses ◽

Hiv 1

ABSTRACT Both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) lead to chronic infection in a high percentage of persons, and an expanding epidemic of HIV-1-HCV coinfection has recently been identified. These individuals provide an opportunity for simultaneous assessment of immune responses to two viral infections associated with chronic plasma viremia. In this study we analyzed the breadth and magnitude of the CD8+- and CD4+-T-lymphocyte responses in 22 individuals infected with both HIV-1 and HCV. A CD8+-T-lymphocyte response against HIV-1 was readily detected in all subjects over a broad range of viral loads. In marked contrast, HCV-specific CD8+-T-lymphocyte responses were rarely detected, despite viral loads in plasma that were on average 1,000-fold higher. The few HCV-specific responses that were observed were relatively weak and limited in breadth. CD4-proliferative responses against HIV-1 were detected in about half of the coinfected subjects tested, but no proliferative response against any HCV protein was found in these coinfected persons. These data demonstrate a major discordance in immune responses to two persistent RNA viruses. In addition, they show a consistent and profound impairment in cellular immune responses to HCV compared to HIV-1 in HIV-1-HCV-coinfected persons.

Download Full-text