Self-Amplifying RNA Vaccine Candidates: Alternative Platforms for mRNA Vaccine Development

Pathogens, Год журнала: 2023, Номер 12(1), С. 138 - 138

Опубликована: Янв. 13, 2023

The present use of mRNA vaccines against COVID-19 has shown for the first time potential infectious diseases. Here we will summarize current knowledge about improved vaccines, i.e., self-amplifying (saRNA) vaccines. This approach may enhance antigen expression by amplification antigen-encoding RNA. RNA design, delivery, and innate immune responses induced be reviewed.

Язык: Английский

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In search of a pan-coronavirus vaccine: next-generation vaccine design and immune mechanisms

Cellular and Molecular Immunology, Год журнала: 2023, Номер 21(2), С. 103 - 118

Опубликована: Дек. 26, 2023

Abstract Members of the coronaviridae family are endemic to human populations and have caused several epidemics pandemics in recent history. In this review, we will discuss feasibility progress toward ultimate goal creating a pan-coronavirus vaccine that can protect against infection disease by all members coronavirus family. We detail unmet clinical need associated with continued transmission SARS-CoV-2, MERS-CoV four seasonal coronaviruses (HCoV-OC43, NL63, HKU1 229E) humans potential for future zoonotic coronaviruses. highlight how first-generation SARS-CoV-2 vaccines natural history studies greatly increased our understanding effective antiviral immunity informed next-generation design. then consider ideal properties propose blueprint type may offer cross-protection. Finally, describe subset diverse technologies novel approaches being pursued developing broadly or universally protective

Язык: Английский

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Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 20, 2024

Abstract Ever-evolving SARS-CoV-2 variants of concern (VOCs) have diminished the effectiveness therapeutic antibodies and vaccines. Developing a coronavirus vaccine that offers greater breadth protection against current future VOCs would eliminate need to reformulate COVID-19 Here, we rationally engineer sequence-conserved S2 subunit spike protein characterize resulting S2-only antigens. Structural studies demonstrate introduction interprotomer disulfide bonds can lock in prefusion trimers, although apex samples continuum conformations between open closed states. Immunization with prefusion-stabilized constructs elicits broadly neutralizing responses several sarbecoviruses protects female BALB/c mice from mouse-adapted lethal challenge partially SARS-CoV challenge. These engineering immunogenicity results should inform development next-generation pan-coronavirus therapeutics

Язык: Английский

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Non-neutralizing SARS-CoV-2 N-terminal domain antibodies protect mice against severe disease using Fc-mediated effector functions

PLoS Pathogens, Год журнала: 2024, Номер 20(6), С. e1011569 - e1011569

Опубликована: Июнь 20, 2024

Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing, yet it protected mice cynomolgus macaques from severe disease. The mechanisms of NTD antibody-mediated protection are unknown. Here we show Fc mediate (non-nAb) MA10 viral challenge in mice. Though non-nAb prophylactic infusion did not suppress infectious titers lung as potently (nAb) infusion, disease markers including gross discoloration were similar nAb groups. functional knockout substitutions abolished increased group. enhancement relative WT, supporting a positive association between functionality degree infection. For therapeutic administration antibodies, contributed virus suppression lessening discoloration, but presence neutralization required for optimal This study demonstrates non-nAbs can utilize Fc-mediated lower load prevent damage due coronavirus

Язык: Английский

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Multivalent S2 subunit vaccines provide broad protection against Clade 1 sarbecoviruses in female mice

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 7, 2025

The continuing emergence of immune evasive SARS-CoV-2 variants and the previous SARS-CoV-1 outbreak collectively underscore need for broadly protective sarbecovirus vaccines. Targeting conserved S2 subunit is a particularly promising approach to elicit broad protection. Here, we describe nanoparticle vaccine displaying multiple copies subunit. This alone, or as cocktail with vaccine, protects female transgenic K18-hACE2 mice from challenges Omicron subvariant XBB well several sarbecoviruses identified having pandemic potential including bat WIV1, BANAL-236, pangolin sarbecovirus. Challenge studies in Fc-γ receptor knockout reveal that antibody-based cellular effector mechanisms play role protection elicited by these These results demonstrate our S2-based vaccines provide against clade 1 offer insight into mechanistic basis Understanding induced cross reactive immunity an important step rationale widely applicable design. Here authors use multivalent SARS-CoV-2-like SARS-CoV-1-like coronaviruses.

Язык: Английский

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A research and development (R&D) roadmap for broadly protective coronavirus vaccines: A pandemic preparedness strategy

Vaccine, Год журнала: 2023, Номер 41(13), С. 2101 - 2112

Опубликована: Фев. 21, 2023

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research Development (R&D) Roadmap (CVR) is aimed at promoting development such vaccines. CVR, funded Bill & Melinda Gates Foundation Rockefeller Foundation, was generated through collaborative iterative process, which led Center Infectious Disease Policy (CIDRAP) University Minnesota involved 50 international subject matter experts recognized leaders field. This report summarizes major issues areas research outlined CVR identifies high-priority milestones. covers 6-year timeframe organized into five topic areas: virology, immunology, vaccinology, animal human infection models, policy finance. Included each area key barriers, gaps, strategic goals, milestones, additional R&D priorities. roadmap includes 20 goals 86 26 ranked as high priority. By identifying issues, milestones addressing them, provides framework to guide funding campaigns that promote broadly

Язык: Английский

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Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

Cell Host & Microbe, Год журнала: 2023, Номер 31(12), С. 1961 - 1973.e11

Опубликована: Ноя. 20, 2023

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with antigenicity their spike (S) glycoproteins remain uncharacterized. Here, we show that African bat sarbecovirus PRD-0038 S has a broad angiotensin-converting enzyme 2 (ACE2) usage and receptor-binding domain (RBD) mutations further expand promiscuity enable human ACE2 utilization. We determine cryo-EM structure RBD bound to alcyone ACE2, explaining highlighting differences SARS-CoV-1 SARS-CoV-2. Characterization using monoclonal antibody reactivity reveals its distinct relative SARS-CoV-2 identifies cross-neutralizing antibodies for pandemic preparedness. vaccination elicits greater titers cross-reacting vaccine-mismatched 1a sarbecoviruses compared due broader antigenic targeting, motivating inclusion antigens in next-generation vaccines enhanced resilience viral evolution.

Язык: Английский

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A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 28, 2024

Abstract Evolution of SARS-CoV-2 alters the antigenicity immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining efficacy vaccines antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing responses on highly conserved but metastable S 2 subunit, which folds as spring-loaded fusion machinery. We describe strategy for prefusion-stabilization high yield recombinant production trimers with native structure antigenicity. demonstrate that our design is broadly generalizable sarbecoviruses, exemplified SARS-CoV-1 (clade 1a) PRD-0038 3) subunits. Immunization mice prefusion-stabilized trimer elicits reactive sarbecovirus antibodies neutralizing titers comparable magnitude against Wuhan-Hu-1 immune evasive XBB.1.5 variant. Vaccinated were protected from weight loss disease upon challenge XBB.1.5, providing proof-of-principle machinery vaccines.

Язык: Английский

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Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 3, 2024

Abstract Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these are protective against homologous coronavirus infection, emergence of novel variants and presence large zoonotic reservoirs harboring heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises risk adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model disease evaluate performance either challenge or bat-derived that represents potential emerging threat. We show can cause during while an alternative adjuvant does not drive promotes viral clearance. In this work, highlight impact selection on safety efficacy infection.

Язык: Английский

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Randomised controlled trial reveals no benefit to a 3-month delay in COVID-19 mRNA booster vaccine

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(17)

Опубликована: Июль 11, 2024

BACKGROUNDThere is uncertainty about the timing of booster vaccination against COVID-19 in highly vaccinated populations during present endemic phase COVID-19. Studies focused on primary have previously suggested improved immunity with a longer interval between first and second vaccine doses.METHODSWe conducted randomized, controlled trial (November 2022-August 2023) assigned 52 fully adults to an immediate or 3-month delayed bivalent Spikevax mRNA vaccine. Follow-up visits were completed for 48 participants (n = 24 per arm), collection saliva plasma samples following each visit.RESULTSThe rise neutralizing antibody responses ancestral Omicron strains almost identical arms. Analyses salivary (IgG, IgA), antibody-dependent phagocytic activity, decay kinetics similar 2 Symptomatic asymptomatic SARS-CoV-2 infections occurred 49% (21 49) over median 11.5 months follow-up also arms.CONCLUSIONSOur data suggest that there was no benefit delaying preimmune COVID-19.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry number 12622000411741 (https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12622000411741).FUNDINGNational Health Medical Research Council, Australia (program grant App1149990) Future Fund (App2005544).

Язык: Английский

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