Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity

John, Shinu; Yuzhakov, Olga; Woods, Angela; Deterling, Jessica; Hassett, Kimberly J.; Shaw, Christine A.; Ciaramella, Giuseppe

doi:10.1016/j.vaccine.2018.01.029

Cited by 169 publications

(144 citation statements)

References 53 publications

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“…64 Moderna Therapeutics has recently published preclinical development of a multiplecomponent HCMV mRNA vaccine consisting of the five constituents of pentameric complex, gB, and pp65. 120 Immunization of mice and nonhuman primates with lipid nanoparticles encapsulating modified mRNA encoding HCMV gBs and pentameric complex elicited potent and durable neutralizing antibody titers, and administration of pp65 vaccine with pentameric complex and gB elicited robust multi-antigenic T-cell responses in mice. 120 While preclinical studies have generated great optimism about the prospects and advantages of mRNA-based vaccines, two recent clinical trials with mRNA-lipid nanoparticle vaccines encoding influenza hemagglutinin and rabies virus glycoprotein have led to more tempered expectations.…”

Section: Rna Hcmv Vaccinesmentioning

confidence: 99%

“…120 Immunization of mice and nonhuman primates with lipid nanoparticles encapsulating modified mRNA encoding HCMV gBs and pentameric complex elicited potent and durable neutralizing antibody titers, and administration of pp65 vaccine with pentameric complex and gB elicited robust multi-antigenic T-cell responses in mice. 120 While preclinical studies have generated great optimism about the prospects and advantages of mRNA-based vaccines, two recent clinical trials with mRNA-lipid nanoparticle vaccines encoding influenza hemagglutinin and rabies virus glycoprotein have led to more tempered expectations. 121,122 In both trials, immunogenicity was more modest in humans than was expected based on animal models, a phenomenon also observed with DNA-based vaccines.…”

Section: Rna Hcmv Vaccinesmentioning

confidence: 99%

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Development of novel vaccines against human cytomegalovirus

Cui

Snapper

2019

Human Vaccines & Immunotherapeutics

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Congenital human cytomegalovirus (HCMV) infection and HCMV infection of the immunosuppressed patients cause significant morbidity and mortality, and vaccine development against HCMV is a major public health priority. Efforts to develop HCMV vaccines have been ongoing for 50 y, though no HCMV vaccine has been licensed; encouraging and promising results have obtained from both preclinical and clinical trials. HCMV infection induces a wide range of humoral and T cell-mediated immune responses, and both branches of immunity are correlated with protection. In recent years, there have been novel approaches toward the development of HCMV vaccines and demonstrated that vaccine candidates could potentially provide superior protection over natural immunity acquired following HCMV infection. Further, rationally designed HCMV protein antigens that express native conformational epitopes could elicit optimal immune response. HCMV vaccine candidates, using a multi-antigen approach, to maximize the elicited protective immunity will most likely be successful in development of HCMV vaccine.

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Section: Rna Hcmv Vaccinesmentioning

confidence: 99%

Section: Rna Hcmv Vaccinesmentioning

confidence: 99%

Development of novel vaccines against human cytomegalovirus

Cui

Snapper

2019

Human Vaccines & Immunotherapeutics

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“…mRNA-vaccinated rabbits appear to have a gB peptide-binding fingerprint that closely resembles that in seropositive individuals elicited by natural host infection [25]. Importantly, while HCMV gB mRNA vaccines have been tested previously in a preclinical model [48], this is the first such investigation to test a gB mRNA-based vaccine alongside the partially-effective gB/MF59 protein subunit vaccination and to directly compare the epitope specificity, durability, and neutralizing/non-neutralizing function of antibodies elicited by these two vaccine platforms.…”

Section: Discussionmentioning

confidence: 99%

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

Nelson

Jenks

Pardi

et al. 2019

Preprint

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2 3 4 HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with 5 greater durability and breadth than MF59-adjuvanted gB protein immunization 6 7 Short Title: Immunogenicity of next-generation HCMV gB vaccines 8 9 Cody 22 23 Abstract WC: 300 (300 max) 24 Author summary WC: 188 (200 max) 25 Main Text WC: 3,177 26 Methods WC: 3,142 2 27 Abstract:28 A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy 29 is a primary strategy to reduce the incidence of congenital disease. Similarly, vaccination of 30 transplant recipients against HCMV has been proposed to prevent transplant-associated HCMV 31 morbidity. The MF59-adjuvanted glycoprotein B protein subunit vaccine (gB/MF59) is the most 32 efficacious tested to-date for both indications. We previously identified that gB/MF59 vaccination 33 elicited poor neutralizing antibody responses and an immunodominant response against gB 34 antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional 35 antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White 36 rabbits were administered 3 sequential doses of full-length gB protein with an MF59-like squalene 37 adjuvant (analogous to clinically-tested vaccine), gB ectodomain protein (lacking AD-3) with 38 squalene adjuvant, or lipid nanoparticle (LNP)-packaged nucleoside-modified mRNA encoding 39 full-length gB. The AD-3 immunodominant IgG response following human gB/MF59 vaccination 40 was closely mimicked in rabbits, with 78% of binding antibodies directed against this region in the 41 full-length gB protein group compared to 1% and 46% in the ectodomain and mRNA-LNP-42 vaccinated groups, respectively. All vaccines were highly immunogenic with similar kinetics and 43 comparable peak gB-binding and functional antibody responses. Although gB ectodomain subunit 44 vaccination reduced targeting of non-neutralizing epitope AD-3, it did not improve vaccine-elicited 45 neutralizing or non-neutralizing antibody functions. gB nucleoside-modified mRNA-LNP-46 immunized rabbits exhibited enhanced durability of IgG binding to soluble and cell membrane-47 associated gB protein as well as HCMV-neutralizing function. Furthermore, the gB mRNA-LNP 48 vaccine enhanced breadth of IgG binding responses against discrete gB peptide residues. Finally, 49 low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-50 LNP vaccine groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest 51 that the gB mRNA-LNP vaccine candidate, aiming to improve upon the partial efficacy of gB/MF59 52 vaccination, should be further evaluated in preclinical models. Author summary:54 Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, 55 resulting in permanent neurologic disability for one newborn child every hour in the United States.56 Furthermore, this virus causes significant morbidity and mortality in immune-suppressed 57 transplant recipients. Af...

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“…Expression may be possible for complex proteins that are difficult or impossible to generate with current expression systems. 1 mRNA constructs can also be used to express potent monoclonal antibodies for novel immunoprophylaxis. 2 Here we review the state of the art in mRNA constructs and delivery technologies for the prevention of infectious diseases, and a review of pertinent topics to the biotechnology and pharmaceutical industries.…”

Section: Introductionmentioning

confidence: 99%

The promise of mRNA vaccines: a biotech and industrial perspective

Jackson¹,

et al. 2020

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mRNA technologies have the potential to transform areas of medicine, including the prophylaxis of infectious diseases. The advantages for vaccines range from the acceleration of immunogen discovery to rapid response and multiple disease target manufacturing. A greater understanding of quality attributes that dictate translation efficiency, as well as a comprehensive appreciation of the importance of mRNA delivery, are influencing a new era of investment in development activities. The application of translational sciences and growing early-phase clinical experience continue to inform candidate vaccine selection.Here we review the state of the art for the prevention of infectious diseases by using mRNA and pertinent topics to the biotechnology and pharmaceutical industries.npj Vaccines (2020) 5:11 ; https://doi.

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Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity

Cited by 169 publications

References 53 publications

Development of novel vaccines against human cytomegalovirus

Development of novel vaccines against human cytomegalovirus

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

The promise of mRNA vaccines: a biotech and industrial perspective

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