scholarly journals SARS-CoV-2 vaccines elicit durable immune responses in infant rhesus macaques

2021 ◽  
Vol 6 (60) ◽  
pp. eabj3684
Author(s):  
Carolina Garrido ◽  
Alan D. Curtis ◽  
Maria Dennis ◽  
Sachi H. Pathak ◽  
Hongmei Gao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Macaques ◽  
Pediatric Population ◽  
Neutralizing Antibody ◽  
Socioeconomic Impacts ◽  
S Protein ◽  
Specific Memory ◽  
Vaccine Schedule ◽  
Igg Binding ◽  
Infant Rhesus

The inclusion of infants in the SARS-CoV-2 vaccine roll-out is important to prevent severe complications of pediatric SARS-CoV-2 infections and to limit transmission and could possibly be implemented via the global pediatric vaccine schedule. However, age-dependent differences in immune function require careful evaluation of novel vaccines in the pediatric population. Toward this goal, we assessed the safety and immunogenicity of two SARS-CoV-2 vaccines. Two groups of 8 infant rhesus macaques (RMs) were immunized intramuscularly at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. Both vaccines elicited high magnitude IgG binding to RBD, N terminus domain, S1, and S2, ACE2 blocking activity, and high neutralizing antibody titers, all peaking at week 6. S-specific memory B cells were detected by week 4 and S-specific T cell responses were dominated by the production of IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. The immune responses for the mRNA-LNP vaccine were of a similar magnitude to those elicited by the Moderna mRNA-1273 vaccine in adults. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines were well-tolerated and highly immunogenic in infant RMs, providing proof-of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity that might decrease the transmission of SARS-CoV-2 and mitigate the ongoing health and socioeconomic impacts of COVID-19.

scholarly journals Immunogenicity, safety, and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Maria Blasi ◽  
Donatella Negri ◽  
Kevin O. Saunders ◽  
Erich J. Baker ◽  
Hannah Stadtler ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Lentiviral Vector ◽  
Rhesus Macaques ◽  
Infected Individual ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Safety And Efficacy ◽  
Env Protein ◽  
Hiv 1

AbstractA preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study, we report the immunogenicity, safety, and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Envs induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/− protein immunizations using the same sequential envelopes. Compared to monkeys immunized with a vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six months after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Although the tested vaccines failed to induce bnAbs and to mediate significant protection following SHIV-challenge, our results show that IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms.

scholarly journals Improved Protection of Rhesus Macaques against Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge by a Replication-Competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag Recombinant Priming/gp120 Boosting Regimen

2003 ◽  
Vol 77 (15) ◽  
pp. 8354-8365 ◽  
Author(s):  
Jun Zhao ◽  
Joel Pinczewski ◽  
Victor R. Gómez-Román ◽  
David Venzon ◽  
V. S. Kalyanaraman ◽  
...  
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
Neutralizing Antibody ◽  
Antibody Activity ◽  
Viral Loads ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Cellular Immune

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.

scholarly journals Oral subunit SARS-CoV-2 vaccine induces systemic neutralizing IgG, IgA and cellular immune responses and can boost neutralizing antibody responses primed by an injected vaccine

2021 ◽  
Author(s):  
Jacob Pitcovski ◽  
Nady Gruzdev ◽  
Anna Abzach ◽  
Chen Katz ◽  
Ran Ben-Adiva ◽  
...  
Keyword(s):  
Immune Responses ◽  
Oral Vaccine ◽  
Protein A ◽  
Surface Protein ◽  
Neutralizing Antibody ◽  
Vaccination Schedule ◽  
Antigenic Drift ◽  
Post Dose ◽  
S Protein ◽  
N Protein

The rapid spread of the COVID-19 pandemic, with its devastating medical and economic impacts, triggered an unprecedented race toward development of effective vaccines. The commercialized vaccines are parenterally administered, which poses logistic challenges, while adequate protection at the mucosal sites of virus entry is questionable. Furthermore, essentially all vaccine candidates target the viral spike (S) protein, a surface protein that undergoes significant antigenic drift. This work aimed to develop an oral multi-antigen SARS-CoV-2 vaccine comprised of the receptor binding domain (RBD) of the viral S protein, two domains of the viral nucleocapsid protein (N), and heat-labile enterotoxin B (LTB), a potent mucosal adjuvant. The humoral, mucosal and cell-mediated immune responses of both a three-dose vaccination schedule and a heterologous subcutaneous prime and oral booster regimen were assessed in mice and rats, respectively. Mice receiving the oral vaccine compared to control mice showed significantly enhanced post-dose-3 virus-neutralizing antibody, anti-S IgG and IgA production and N-protein-stimulated IFN-γand IL-2 secretion by T cells. When administered as a booster to rats following parenteral priming with the viral S1 protein, the oral vaccine elicited markedly higher neutralizing antibody titres than did oral placebo booster. A single oral booster following two subcutaneous priming doses elicited serum IgG and mucosal IgA levels similar to those raised by three subcutaneous doses. In conclusion, the oral LTB-adjuvanted multi-epitope SARS-CoV-2 vaccine triggered versatile humoral, cellular and mucosal immune responses, which are likely to provide protection, while also minimizing technical hurdles presently limiting global vaccination, whether by priming or booster programs.

scholarly journals Adjuvant-Dependent Enhancement of HIV Env-Specific Antibody Responses in Infant Rhesus Macaques

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Bonnie Phillips ◽  
Koen K. A. Van Rompay ◽  
Jennifer Rodriguez-Nieves ◽  
Clarisse Lorin ◽  
Marguerite Koutsoukos ◽  
...  
Keyword(s):  
Immune Responses ◽  
Specific Antibody ◽  
Hiv Transmission ◽  
Rhesus Macaques ◽  
Pediatric Population ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Igg Antibody ◽  
Macaque Model ◽  
Pediatric Vaccines

ABSTRACTToward the goal of developing an effective HIV vaccine that can be administered in infancy to protect against postnatal and lifelong sexual HIV transmission risks, the current pilot study was designed to compare the effect of novel adjuvants on the induction of HIV Env-specific antibody responses in infant macaques. Aligning our studies with the adjuvanted proteins evaluated in a prime-boost schedule with ALVAC in the ongoing HVTN (HIV Vaccine Trials Network) 702 efficacy trial, we selected the bivalent clade C Env immunogens gp120 C.1086 and gp120 TV1 in combination with the MF59 adjuvant. However, we hypothesized that the adjuvant system AS01, that is included in the pediatric RTS,S malaria vaccine, would promote Env-specific antibody responses superior to those of the oil-in-water MF59 emulsion adjuvant. In a second study arm, we compared two emulsions, glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) and 3M-052-SE, containing Toll-like receptor 4 (TLR4) and TLR7/TLR8 (TLR7/8) ligand, respectively. The latter adjuvant had been previously demonstrated to be especially effective in activating neonatal antigen-presenting cells. Our results demonstrate that different adjuvants drive quantitatively or qualitatively distinct responses to the bivalent Env vaccine. AS01 induced higher Env-specific plasma IgG antibody levels than the antigen in MF59 and promoted improved antibody function in infants, and 3M-052-SE outperformed GLA-SE by inducing the highest breadth and functionality of antibody responses. Thus, distinct adjuvants are likely to be required for maximizing vaccine-elicited immune responses in infants, particularly when immunization in infancy aims to elicit both perinatal and lifelong immunity against challenging pathogens such as HIV.IMPORTANCEAlum remains the adjuvant of choice for pediatric vaccines. Yet the distinct nature of the developing immune system in infants likely requires novel adjuvants targeted specifically at the pediatric population to reach maximal vaccine efficacy with an acceptable safety profile. The current study supports the idea that additional adjuvants for pediatric vaccines should be, and need to be, tested in infants for their potential to enhance immune responses. Using an infant macaque model, our results suggest that both AS01 and 3M-052-SE can significantly improve and better sustain HIV Env-specific antibody responses than alum. Despite the limited number of animals, the results revealed interesting differences that warrant further testing of promising novel adjuvant candidates in larger preclinical and clinical studies to define the mechanisms leading to adjuvant-improved antibody responses and to identify targets for adjuvant and vaccine optimization.

scholarly journals Use of Vaxfectin Adjuvant with DNA Vaccine Encoding the Measles Virus Hemagglutinin and Fusion Proteins Protects Juvenile and Infant Rhesus Macaques against Measles Virus

2008 ◽  
Vol 15 (8) ◽  
pp. 1214-1221 ◽  
Author(s):  
Chien-Hsiung Pan ◽  
Gretchen S. Jimenez ◽  
Nitya Nair ◽  
Qun Wei ◽  
Robert J. Adams ◽  
...  
Keyword(s):  
Measles Virus ◽  
Rhesus Macaques ◽  
Cationic Lipid ◽  
Neutralizing Antibody ◽  
Interleukin 4 ◽  
Measles Vaccine ◽  
Young Infants ◽  
Ifn Γ ◽  
Full Protection ◽  
Infant Rhesus

ABSTRACT A measles virus vaccine for infants under 6 months of age would help control measles. DNA vaccines hold promise, but none has provided full protection from challenge. Codon-optimized plasmid DNAs encoding the measles virus hemagglutinin and fusion glycoproteins were formulated with the cationic lipid-based adjuvant Vaxfectin. In mice, antibody and gamma interferon (IFN-γ) production were increased by two- to threefold. In macaques, juveniles vaccinated at 0 and 28 days with 500 μg of DNA intradermally or with 1 mg intramuscularly developed sustained neutralizing antibody and H- and F-specific IFN-γ responses. Infant monkeys developed sustained neutralizing antibody and T cells secreting IFN-γ and interleukin-4. Twelve to 15 months after vaccination, vaccinated monkeys were protected from an intratracheal challenge: viremia was undetectable by cocultivation and rashes did not appear, while two naïve monkeys developed viremia and rashes. The use of Vaxfectin-formulated DNA is a promising approach to the development of a measles vaccine for young infants.

scholarly journals Different adjuvanted pediatric HIV envelope vaccines induced distinct plasma antibody responses despite similar B cell receptor repertoires in infant rhesus macaques.

2021 ◽  
Author(s):  
Genevieve G. Fouda ◽  
Stella J Berendam ◽  
Papa K Morgan-Asiedu ◽  
Riley J Mangan ◽  
Shukhang Li ◽  
...  
Keyword(s):  
B Cell ◽  
Rhesus Macaques ◽  
Cell Receptor ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Pediatric Hiv ◽  
Specific Memory ◽  
Plasma Antibody ◽  
Hiv Envelope ◽  
Infant Rhesus

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein coadministered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.

scholarly journals SARS-CoV-2 Vaccines Elicit Durable Immune Responses in Infant Rhesus Macaques

2021 ◽  
Author(s):  
Carolina Garrido ◽  
Alan D. Curtis ◽  
Maria Dennis ◽  
Sachi H. Pathak ◽  
Hongmei Gao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protective Immunity ◽  
Rhesus Macaques ◽  
Herd Immunity ◽  
Cellular Responses ◽  
Infectious Dose ◽  
Vaccine Candidates ◽  
Cell Responses ◽  
High Magnitude ◽  
Infant Rhesus

AbstractEarly life SARS-CoV-2 vaccination has the potential to provide lifelong protection and achieve herd immunity. To evaluate SARS-CoV-2 infant vaccination, we immunized two groups of 8 infant rhesus macaques (RMs) at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein, either encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or mixed with 3M-052-SE, a TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. High magnitude S-binding IgG and neutralizing infectious dose 50 (ID50) >103 were elicited by both vaccines. S-specific T cell responses were dominated by IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines are promising pediatric SARS-CoV-2 vaccine candidates to achieve durable protective immunity.One-Sentence SummarySARS-CoV-2 vaccines are well-tolerated and highly immunogenic in infant rhesus macaques

scholarly journals DNA vaccine protection against SARS-CoV-2 in rhesus macaques

Science ◽  
2020 ◽  
Vol 369 (6505) ◽  
pp. 806-811 ◽  
Author(s):  
Jingyou Yu ◽  
Lisa H. Tostanoski ◽  
Lauren Peter ◽  
Noe B. Mercado ◽  
Katherine McMahan ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Vaccine Protection ◽  
S Protein ◽  
Viral Loads ◽  
Cellular Immune Responses ◽  
Antibody Titers ◽  
Cellular Immune

The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.

scholarly journals COVID-eVax, an electroporated plasmid DNA vaccine candidate encoding the SARS-CoV-2 Receptor Binding Domain, elicits protective immune responses in animal models of COVID-19

2021 ◽  
Author(s):  
Antonella Conforti ◽  
Emanuele Marra ◽  
Fabio Palombo ◽  
Giuseppe Roscilli ◽  
Micol Rava ◽  
...  
Keyword(s):  
Animal Models ◽  
Immune Responses ◽  
Vaccine Candidate ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Common Variants ◽  
S Protein ◽  
Global Priority ◽  
Plasmid Dna Vaccine ◽  
Dna Plasmid

The COVID-19 pandemic caused by the β-coronavirus SARS-CoV-2 has made the development of safe and effective vaccines a critical global priority. To date, four vaccines have already been approved by European and American authorities for preventing COVID-19 but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle, a technology previously utilized for cancer vaccines. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 Spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax – a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein RBD – induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function and significantly lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started in Italy.

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