Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates

AbstractDevelopment of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we found that mRNA-LNP immunization compared to protein immunization elicited either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope (prM-E) or HIV-1 Env gp160 induced durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 μg were immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

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Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates

npj Vaccines ◽

10.1038/s41541-021-00307-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Kevin O. Saunders ◽

Norbert Pardi ◽

Robert Parks ◽

Sampa Santra ◽

Zekun Mu ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Nonhuman Primates ◽

Lipid Nanoparticles ◽

Preclinical Studies ◽

Critical Question ◽

Aids Vaccine ◽

Vaccine Immunogenicity ◽

Protein Vaccines ◽

Protein Immunization ◽

Hiv 1

AbstractThe development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 μg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

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Progress in the rational design of an AIDS vaccine

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2011.0096 ◽

2011 ◽

Vol 366 (1579) ◽

pp. 2759-2765 ◽

Cited By ~ 32

Author(s):

Gary J. Nabel ◽

Peter D. Kwong ◽

John R. Mascola

Keyword(s):

Structural Biology ◽

Neutralizing Antibodies ◽

Rational Design ◽

Computational Modelling ◽

Effective Vaccine ◽

Aids Vaccine ◽

Immunodeficiency Virus ◽

High Degree ◽

Hiv 1 ◽

Human Immunodeficiency Virus 1

Human immunodeficiency virus-1 (HIV-1) has a high degree of genetic and antigenic diversity that has impeded the development of an effective vaccine using traditional methods. We are attempting to develop an AIDS vaccine by employing strategies that include structural biology and computational modelling, in an effort to develop immunogens capable of eliciting neutralizing antibodies of the requisite breadth and potency against circulating strains of HIV-1.

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Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gp120 from the MN strain of HIV-1. NIAID AIDS Vaccine Clinical Trials Network

JAMA ◽

10.1001/jama.272.6.475 ◽

1994 ◽

Vol 272 (6) ◽

pp. 475-480 ◽

Cited By ~ 34

Author(s):

R. B. Belshe

Keyword(s):

Clinical Trials ◽

Neutralizing Antibodies ◽

Recombinant Gp120 ◽

Aids Vaccine ◽

Hiv 1

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Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

Science ◽

10.1126/science.aan8630 ◽

2017 ◽

Vol 358 (6359) ◽

pp. 85-90 ◽

Cited By ~ 135

Author(s):

Ling Xu ◽

Amarendra Pegu ◽

Ercole Rao ◽

Nicole Doria-Rose ◽

Jochen Beninga ◽

...

Keyword(s):

Single Molecule ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Aids Vaccine ◽

Single Protein ◽

Hiv Antibodies ◽

Cd4 Binding Site ◽

Human Immunodeficiency Viruses ◽

Glycan Site ◽

Hiv 1

The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

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Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.01247-13 ◽

2013 ◽

Vol 87 (24) ◽

pp. 13239-13251 ◽

Cited By ~ 50

Author(s):

B. K. Chakrabarti ◽

Y. Feng ◽

S. K. Sharma ◽

K. McKee ◽

G. B. Karlsson Hedestam ◽

...

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Nonhuman Primates ◽

Hiv 1

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V3-specific neutralizing antibodies in sera from HIV-1 gp160-immunized volunteers block virus fusion and act synergistically with human monoclonal antibody to the conformation-dependent CD4 binding site of gp120. NIH-NIAID AIDS Vaccine Clinical Trials Network.

Journal of Clinical Investigation ◽

10.1172/jci116658 ◽

1993 ◽

Vol 92 (2) ◽

pp. 840-847 ◽

Cited By ~ 43

Author(s):

D C Montefiori ◽

B S Graham ◽

J Zhou ◽

R A Bucco ◽

...

Keyword(s):

Monoclonal Antibody ◽

Clinical Trials ◽

Binding Site ◽

Neutralizing Antibodies ◽

Human Monoclonal Antibody ◽

Aids Vaccine ◽

Virus Fusion ◽

Cd4 Binding Site ◽

Hiv 1

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Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.01265-15 ◽

2015 ◽

Vol 89 (16) ◽

pp. 8525-8539 ◽

Cited By ~ 28

Author(s):

Juan García-Arriaza ◽

Beatriz Perdiguero ◽

Jonathan Heeney ◽

Michael Seaman ◽

David C. Montefiori ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Nonhuman Primates ◽

Humoral Immune ◽

Aids Vaccine ◽

Humoral Immune Responses ◽

Gp120 Protein ◽

Clade C ◽

Hiv 1 ◽

Hiv Aids

ABSTRACTWe compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4+T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8+T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade C HIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVAC versus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine.IMPORTANCEThe finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials.

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Sustained Delivery of a Broadly Neutralizing Antibody in Nonhuman Primates Confers Long-Term Protection against Simian/Human Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.00210-15 ◽

2015 ◽

Vol 89 (11) ◽

pp. 5895-5903 ◽

Cited By ~ 67

Author(s):

Kevin O. Saunders ◽

Amarendra Pegu ◽

Ivelin S. Georgiev ◽

Ming Zeng ◽

M. Gordon Joyce ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Infection ◽

Neutralizing Antibodies ◽

Nonhuman Primates ◽

Human Antibody ◽

Protective Capacity ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Passive Antibody Transfer

ABSTRACTPathogen-specific neutralizing antibodies protect against many viral infections and can potentially prevent human immunodeficiency virus (HIV) transmission in humans. However, neutralizing antibodies have so far only been shown to protect nonhuman primates (NHP) against lentiviral infection when given shortly before challenge. Thus, the clinical utility and feasibility of passive antibody transfer to confer long-term protection against HIV-1 are still debated. Here, we investigate the potential of a broadly neutralizing HIV-1 antibody to provide long-term protection in a NHP model of HIV-1 infection. A human antibody was simianized to avoid immune rejection and used to sustain therapeutic levels for ∼5 months. Two months after the final antibody administration, animals were completely protected against viral challenge. These findings demonstrate the feasibility and potential of long-term passive antibody for protection against HIV-1 in humans and provide a model to test antibody therapies for other diseases in NHP.IMPORTANCEAntibodies against HIV are potential drugs that may be able to prevent HIV infection in humans. However, the long-term protective capacity of antibodies against HIV has not been assessed. Here, we repetitively administered a macaque version of a human anti-HIV antibody to monkeys, after which the antibody persisted in the blood for >5 months. Moreover, the antibody could be sustained at protective levels for 108 days, conferring protection 52 days after the last dose in a monkey model of HIV infection. Thus, passive antibody transfer can provide durable protection against infection by viruses that cause AIDS in primates.

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HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.02182-16 ◽

2017 ◽

Vol 91 (9) ◽

Cited By ~ 16

Author(s):

Juan García-Arriaza ◽

Beatriz Perdiguero ◽

Jonathan L. Heeney ◽

Michael S. Seaman ◽

David C. Montefiori ◽

...

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Vaccine Candidates ◽

Aids Vaccine ◽

Clade C ◽

Hiv 1 ◽

Hiv Aids

ABSTRACT The nonreplicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120) and Gag-Pol-Nef antigens (NYVAC-C) showed limited immunogenicity in phase I clinical trials. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4+ and CD8+ T cells, here we compared the HIV-1-specific immunogenicity elicited in nonhuman primates immunized with two replicating NYVAC vectors that have been modified by the insertion of the K1L and C7L vaccinia virus host range genes and express the clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral gene B19R, an inhibitor of the type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking that of the RV144 phase III clinical trial was used. Two groups of macaques received two doses of the corresponding NYVAC-C-KC vectors (weeks 0 and 4) and booster doses with NYVAC-C-KC vectors plus the clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced enhanced and similar HIV-1-specific CD4+ and CD8+ T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, and high levels of antibody-dependent cellular cytotoxicity responses and HIV-1-neutralizing antibodies. Small differences within the NYVAC-C-KC-ΔB19R group were seen in the magnitude of CD4+ and CD8+ T cells, the induction of some cytokines, and the neutralization of some HIV-1 isolates. Thus, replication-competent NYVAC-C-KC vectors acquired relevant immunological properties as vaccine candidates against HIV/AIDS, and the viral B19 molecule exerts some control of immune functions. IMPORTANCE It is of special importance to find a safe and effective HIV/AIDS vaccine that can induce strong and broad T cell and humoral immune responses correlating with HIV-1 protection. Here we developed novel replicating poxvirus NYVAC-based HIV/AIDS vaccine candidates expressing clade C HIV-1 antigens, with one of them lacking the vaccinia virus B19 protein, an inhibitor of the type I interferon response. Immunization of nonhuman primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited high levels of T cell and humoral immune responses, with the vector containing a deletion in B19R inducing a trend toward a higher magnitude of CD4+ and CD8+ T cell responses and neutralization of some HIV-1 strains. These poxvirus vectors could be considered HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.

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