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Abstract:
This episode of "This Week in Virology" (TwIV 1209) covers recent virology news, listener feedback, and features detailed discussions on two pre-print papers concerning Norovirus vaccines and antibodies. News items include critiques of RFK Jr.'s comments on Novavax vaccines and autism deadlines, and a mention of Colossal Bioscience's "dire wolf" announcement. The first main discussion centers on a Phase 1 clinical trial of an oral, Ad5-vectored Norovirus vaccine (VXA-G1.1 containing VP1 and a dsRNA adjuvant) developed by Vaxart. The trial assessed safety and immunogenicity in older adults (55-80), finding the vaccine safe and capable of inducing durable systemic (serum IgG, IgA, T-cells) and mucosal (salivary, nasal IgA) immune responses, including antibodies that block virus-like particle binding. The second paper delves into identifying broadly neutralizing antibodies against Norovirus G2 genotypes, particularly the prevalent G2.4 variants. Using sophisticated techniques like mass spectrometry, sequencing, and structural biology on samples from individuals vaccinated with a G2.4 Vaxart vaccine, researchers characterized potent antibodies. Notably, antibody VX-22 demonstrated broad neutralization across multiple G2 genotypes, potentially by inducing virus particle disassembly, highlighting promising targets for future vaccine design and therapeutic development. The episode concludes with listener emails and picks of the week.
TWIV 1209: Tackling Norovirus with Vaccines and Antibodies
0:00 Introduction & Weather: Hosts introduce the episode, guests, and share current weather conditions.
0:02 Support & ASV News: A reminder about supporting MicrobeTV and updates on upcoming deadlines for the American Society for Virology (ASV) meeting (ASV Cares/Kitty Corp: May 9th, Early Bird Registration: May 12th).
0:03 News: Novavax & RFK Jr.: Discussion on Novavax stock selloff following RFK Jr.'s inaccurate comments claiming single-antigen vaccines don't work, contradicting evidence for COVID-19, Shingrix, and RSV vaccines. Frustration over Novavax's EUA status despite data.
0:06 News: Dire Wolves: Follow-up on Colossal Bioscience's PR announcement about "resurrecting" dire wolves, clarifying they are genetically engineered gray wolves, not true resurrected dire wolves, and lack peer-reviewed data. Includes a humorous Jurassic Park reference.
0:08 News: Autism Deadline & RFK Jr.: Critique of RFK Jr. setting a deadline to identify the cause of rising autism rates, highlighting the complexity of autism genetics and the flawed premise of a recent, dramatic rise (confounding diagnosis with incidence).
0:10 Introduction to Norovirus Papers: Setting the stage for discussing Norovirus, its impact, and challenges in vaccine development due to diversity. Recalls Dixon Despommier's Norovirus/Norwalk story.
0:11 Paper 1 (Snippet): Vaxart Oral Vaccine Phase 1: Introduction to the first paper detailing a Phase 1 trial of Vaxart's oral, Ad5-based Norovirus vaccine (VXA-G1.1) in older adults (55-80).
0:13 Vaccine Platform Details: The vaccine is a thermostable, enteric-coated oral tablet using a non-replicating Ad5 vector expressing Norovirus G1.1 VP1 and a dsRNA adjuvant, designed to target the intestinal ileum.
0:14 Trial Overview & Goal: Randomized, placebo-controlled trial aimed primarily at assessing safety and tolerability in an older population, building on previous data in younger adults. Focus on addressing the "vaccine efficacy gap" in the elderly, who suffer the most mortality.
0:21 Safety Findings: The vaccine was well-tolerated, with only mild-to-moderate solicited adverse events (headache, malaise, fatigue) occurring at similar rates in vaccine and placebo groups. Unsolicited events were also similar between groups.
0:24 Serum Antibody Responses: Vaccination induced significant increases in serum IgA and IgG antibodies against VP1, which remained elevated at day 210. Responses were comparable between age groups (55-65 vs 66-80).
0:27 Surrogate Neutralization & Avidity: The vaccine elicited serum antibodies that block VLP binding to histo-blood group antigens (a surrogate for neutralization). Antibody avidity (binding strength) increased over time.
0:28 Role of IgA: Analysis suggests serum IgA contributes more significantly to the VLP-blocking activity than serum IgG.
0:30 B Cell Responses: The vaccine induced antibody-secreting B cells (ASCs) in the blood, including IgA-producing plasma blasts with gut-homing potential, with no difference between age groups.
0:32 Mucosal Antibody Responses: Significant increases in VP1-specific IgA were detected in saliva and nasal lining fluid post-vaccination, remaining elevated at day 210, indicating induction of distal mucosal immunity.
0:37 Vaccine Potential & Future: Discussion on the promise of this oral platform, potential target populations (elderly, congregate settings), and the ongoing Phase 2 trial using a bivalent (G1.1 + G2.4) vaccine.
0:41 Paper 2: Broadly Neutralizing Antibodies: Introduction to the second paper focusing on identifying broadly neutralizing antibodies against pandemic Norovirus G2 variants, especially G2.4.
0:42 Norovirus Background: Reinforces the global burden of Norovirus, the dominance of G2 genotypes (especially G2.4), and the challenge posed by antigenic diversity. Evidence suggests long-term protective immunity is possible.
0:43 Study Approach: Researchers analyzed responses in two individuals vaccinated with Vaxart's Ad5-based G2.4 VP1 oral vaccine, selected for their robust and broad neutralizing serum responses.
0:53 Participant Responses & Imprinting: Participant A showed broad G2.4 neutralization, while Participant B had pre-existing cross-genotype (G2 and G1) neutralization breadth. Vaccination boosted responses, with evidence suggesting immune imprinting based on responses to ancestral vs. vaccine strains.
0:55 Deep Dive into Antibody Repertoires: Sophisticated methods (mass spec, single-cell sequencing) were used to deconvolute the antigen-specific antibody repertoires, identifying dominant clonotypes.
0:57 "Back Boosting" & Memory: Vaccination boosted pre-existing antibody clonotypes ("back boosting"), indicating recall responses from memory B cells elicited by prior infections.
1:01 Characterizing Monoclonal Antibodies (Participant A): Recombinantly expressed monoclonal antibodies revealed two classes: Class 1 neutralized most G2.4 variants except HK 2019; Class 2 neutralized all, including HK 2019, by targeting more conserved epitopes.
1:05 Neutralization Mechanism (Class 1 & 2): Neutralization assays using intestinal organoids confirmed blocking activity. Class 1 antibodies likely hinder ligand binding, while Class 2 may use allosteric mechanisms.
1:07 Characterizing Monoclonal Antibodies (Participant B): Analysis identified potent antibodies VX20 and VX-22, which block multiple G2 genotypes and neutralize virus replication in organoids.
1:08 Antibody Evolution Trajectory: Phylogenetic analysis traced the likely development pathway of VX-22, showing mutations in both light (VL) and heavy (VH) chains contributed to its broad neutralization capacity, likely driven by sequential exposures.
1:13 Structural Analysis of VX-22: Crystallography revealed the VX-22 epitope is distant from ligand-binding sites.
1:14 VX-22 Mechanism: Particle Disassembly: Electron microscopy showed VX-22 binding leads to the disruption/disassembly of virus particles, explaining its potent and broad activity despite binding away from functional sites.
1:16 Therapeutic Potential: VX-22 and similar antibodies are identified as promising candidates for prophylaxis or treatment against Norovirus.
1:18 Email: Dementia & Vaccines: Listener shares an Australian article providing background on the research linking vaccines (like shingles) to reduced dementia risk.
1:19 Email: Shingles Vaccine Timing: Listener shares experience with early shingles outbreaks and asks about getting Shingrix early, linking to the dementia discussion.
1:21 Email: Listener from Guadeloupe: Listener shares appreciation for the podcast, connects the "pluviosity" episode title to the French Republican calendar, and mentions local scientific discoveries (Thiomargarita magnifica).
1:24 Email: Measles Monoclonals: Listener proposes using monoclonal antibodies for measles post-exposure prophylaxis and potentially for infants under 12 months in outbreak settings, questioning potential interference with vaccination.
1:31 Pick: Yuri-Miller Experiment Update: Research showing basic organic molecules (uracil, glycine) can form from early Earth chemicals using electron transfer between water droplets ("micro-lightning"/static electricity), updating the classic experiment.
1:31 Pick: Viewing the ISS: Astronomy Picture of the Day showing the ISS transiting Venus, with links to resources (NASA alerts, apps like GoISSWatch) for spotting the space station.
1:34 Pick: Mason Bees: Article highlighting Mason bees as efficient native pollinators that are solitary, don't sting, and can be encouraged with bee houses, potentially helping offset honeybee declines.
1:36 Pick: Medieval Manuscript Covers: Research using ancient DNA and collagen analysis reveals 12th/13th-century Cistercian manuscript covers were often made from seal skins, indicating medieval trade routes.
1:39 Listener Pick: Ride Operator Pranks: Link to videos of an amusement park ride operator pranking riders.