Compendium

Virology and Vaccine Platforms

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Virology and Vaccine Platforms

A Tier 2 specialty covering virus biology, the modern viral threat landscape, and the manufacturing platforms (inactivated, attenuated, subunit, conjugate, viral-vector, mRNA, saRNA, DNA, VLP) that translate viral antigens into licensed vaccines. The post-COVID era (2021-2026) reshaped the field — mRNA matured from academic platform to multi-product modality, RSV finally yielded licensed vaccines, malaria reached the first WHO-recommended vaccine, and pandemic preparedness for “Disease X” became a structured global program (CEPI, BARDA, WHO R&D Blueprint).

Virus classification

The Baltimore classification (David Baltimore 1971; Nobel 1975) organizes viruses by their genome and replication strategy:

  • I. dsDNA — herpesviruses, adenoviruses, poxviruses, papillomaviruses, polyomaviruses, asfarviruses.
  • II. ssDNA — parvoviruses (B19, AAV), circoviruses, anelloviruses.
  • III. dsRNA — reoviruses (rotavirus), birnaviruses.
  • IV. (+)ssRNA — picornaviruses (polio, rhinovirus, EV-D68, FMDV), coronaviruses (SARS-CoV-1/2, MERS-CoV, HKU1, OC43), flaviviruses (dengue 1-4, Zika, JEV, YFV, WNV, TBEV), togaviruses (chikungunya, EEEV, VEEV), caliciviruses (norovirus), hepeviruses (HEV), HCV.
  • V. (−)ssRNA — orthomyxoviruses (influenza A/B/C/D), paramyxoviruses (measles, mumps, RSV, hMPV, Nipah, Hendra), pneumoviruses, filoviruses (Ebola, Marburg, Bombali), rhabdoviruses (rabies, VSV), bunyaviruses (hantavirus, CCHF, Rift Valley fever, La Crosse, SFTSV), arenaviruses (Lassa, LCMV, Junin).
  • VI. (+)ssRNA with reverse transcriptase — retroviruses (HIV-1/2, HTLV-1, MLV, foamy virus).
  • VII. dsDNA with reverse transcriptase — hepadnaviruses (HBV), caulimoviruses (plant).

ICTV (International Committee on Taxonomy of Viruses) maintains the official taxonomy; ~14,000 species characterized by 2024. Metagenomics is rapidly expanding the catalog (RNA virome studies of Wolbachia, soil, ocean).

Major viral families and threats

Cross-link microbiology-foundations. Selected pathogen highlights:

  • Coronaviruses — alpha (HCoV-229E, NL63), beta (OC43, HKU1, SARS-CoV-1, MERS-CoV, SARS-CoV-2), gamma/delta (animal). Spike (S) protein cleaved by furin and TMPRSS2; ACE2 receptor for SARS-CoV-2, DPP4 for MERS-CoV.
  • Influenza — A (HA H1-H18 × NA N1-N11; reassortment; pandemic potential), B (Yamagata extinct post-2020 per WHO; Victoria remains), C, D. Sialic acid receptors (α2,6 human; α2,3 avian). H5N1 clade 2.3.4.4b 2024-25 dairy cattle outbreak Texas → Michigan → Colorado → 60+ confirmed human cases (mostly mild conjunctivitis; one death Louisiana Jan 2025); USDA-FDA-CDC coordinated response; raw milk reservoir; H5N1 vaccine stockpile activated.
  • Flaviviruses — dengue 1-4 (~390M infections/year globally), Zika (2015-16 Americas outbreak; congenital syndrome), yellow fever, JEV, WNV, tick-borne encephalitis. Dengvaxia controversy (Sanofi; serotype-specific risks).
  • Filoviruses — Ebola Zaire (most virulent; multiple DRC outbreaks), Sudan, Bundibugyo, Marburg (Rwanda outbreak 2024-25). Ervebo and Zabdeno/Mvabea vaccines licensed for EBOV.
  • Paramyxoviruses — measles (R0 12-18; vaccine elimination targets), mumps, RSV (winter epidemic; major infant and elderly burden), Nipah (Bangladesh outbreaks; fruit bat reservoir; 70%+ CFR), Hendra (Australia equine/human).
  • Picornaviruses — polio (wild type 2 and 3 eradicated; type 1 endemic in Afghanistan and Pakistan only; cVDPV ongoing — circulating vaccine-derived poliovirus from OPV; nOPV2 deployment 2021-onward to interrupt cVDPV2), enterovirus D68 (acute flaccid myelitis), rhinovirus.
  • Herpesviruses — HSV-1/2, VZV (chickenpox/shingles), EBV (mononucleosis; Burkitt lymphoma; nasopharyngeal carcinoma; multiple sclerosis association Bjornevik 2022 Science), CMV (congenital infection leading cause hearing loss), HHV-6/7/8 (KSHV/Kaposi).
  • Papillomaviruses — HPV; 14 high-risk types cause >90% cervical cancers and most anal, oropharyngeal cancers.
  • Reoviruses — rotavirus (major pediatric diarrhea; pre-vaccine ~500k deaths/yr globally).
  • Togaviruses — chikungunya (Indian Ocean outbreak 2005-06; Americas 2013+; Ixchiq vaccine Valneva approved 2023).
  • Bunyaviruses — hantavirus (Sin Nombre US; HPS), CCHF Crimean-Congo HF (R0 modest; tick-borne; Iran/Turkey/Balkans), Rift Valley fever, SFTSV emerging China/Japan/Korea.
  • Bacteriophages — phage therapy resurgent against MDR bacteria (Locus Biosciences, Adaptive Phage Therapeutics, BiomX, SNIPR Biome). Eligo Bioscience programmable CRISPR-Cas systems.

Pandemic preparedness

WHO R&D Blueprint priority pathogens (updated 2024): COVID-19, Crimean-Congo HF, Ebola/Marburg, Lassa, MERS, SARS, Nipah/henipa, RVF, Zika, mpox, and “Disease X” as a placeholder for novel emergent threats. The blueprint specifies prioritized R&D pathways, sample sharing, and target product profiles.

mpox clade Ib emergence in DRC 2023-24 → WHO PHEIC (Public Health Emergency of International Concern) declared August 2024; Africa CDC PHE simultaneous. MVA-BN (Jynneos / Imvanex / Imvamune; Bavarian Nordic) and ACAM2000 deployed. Clade Ib sustained sexual transmission; pediatric severity higher than 2022 clade IIb outbreak.

Avian influenza — see H5N1 dairy outbreak above. Audenz (Seqirus H5N1) and BARDA-stockpiled pre-pandemic vaccines available; mRNA H5N1 vaccines (Moderna mRNA-1018, Pfizer) advanced in 2024-25 to Phase 3.

Vaccine platforms

Inactivated (whole-killed)

Replication-incompetent whole virus chemically inactivated (formalin, β-propiolactone). Generates broad antigenic response but Th2-biased; multiple doses typically required.

  • Salk polio IPV (Jonas Salk 1955) — formalin-inactivated; foundational success.
  • Hepatitis A — Havrix (GSK), Vaqta (Merck).
  • Influenza — Fluzone, Flucelvax, Afluria; high-dose Fluzone HD and adjuvanted Fluad for ≥65; trivalent post-Yamagata extinction.
  • Rabies — Verorab, Imovax.
  • Japanese encephalitis — Ixiaro (Valneva).
  • Tick-borne encephalitis — FSME-Immun (Pfizer), Encepur (Bavarian Nordic).
  • SARS-CoV-2 — CoronaVac (Sinovac), BBIBP-CorV (Sinopharm), Covaxin BBV152 (Bharat Biotech), Valneva VLA2001, KoviVax (Russia).

Live attenuated

Replicating virus passaged in non-human cells until pathogenicity reduced. Strong durable immunity (often lifelong); usually contraindicated in immunocompromised or pregnancy.

  • Sabin polio OPV (1961) — three strains; trivalent OPV phased to bivalent (2016) due to cVDPV2 risk; mOPV2 and nOPV2 for outbreak response.
  • MMR — Edmonston-Enders measles; Jeryl Lynn mumps; Wistar rubella RA 27/3.
  • Varicella — Varivax (Oka strain; Takahashi 1974).
  • Yellow fever 17D (Max Theiler 1937; Nobel 1951).
  • Rotavirus — RotaTeq (Merck; bovine-human reassortant), Rotarix (GSK; attenuated human G1P[8]).
  • Smallpox — vaccinia Dryvax, ACAM2000, MVA-BN third-gen.
  • Intranasal influenza — FluMist / Fluenz (LAIV).
  • Dengue — Dengvaxia (Sanofi; restricted use seropositive only), Qdenga (Takeda 2022 EU/UK approval).

Subunit recombinant protein

Purified antigen (often a single protein, sometimes assembled into nanoparticle). Lower reactogenicity; multiple doses usually needed.

  • Hepatitis B — Recombivax HB (Merck 1986; first recombinant vaccine in humans), Engerix-B (GSK), Heplisav-B (Dynavax with CpG 1018 adjuvant).
  • HPV — Gardasil 9 (Merck; nonavalent L1 VLP types 6/11/16/18/31/33/45/52/58), Cervarix (GSK bivalent 16/18; with AS04).
  • Pertussis acellular — multiple components (PT, FHA, pertactin, FIM).
  • Meningococcal B — Bexsero (GSK; 4 antigens including factor H-binding protein), Trumenba (Pfizer; bivalent fHbp).
  • Novavax COVID — NVX-CoV2373 / Covovax (recombinant spike trimer on nanoparticle + Matrix-M adjuvant).
  • Shingles — Shingrix (GSK; gE glycoprotein + AS01_B adjuvant; >90% efficacy in elderly).
  • RSV — Arexvy (GSK 2023 adults ≥60) and Abrysvo (Pfizer 2023 adults ≥60 and maternal immunization 32-36 wk to protect infant). Both PreF-stabilized (McLellan-Graham VRC technology; landmark structural-biology-enabled vaccine).

Toxoid

Inactivated bacterial toxin — diphtheria, tetanus (combined as DT, DTaP, Tdap, Td). Cholera toxin B-subunit included in Dukoral oral.

Conjugate (polysaccharide-protein)

Conjugation of capsular polysaccharide to carrier protein (CRM197, TT, DT) recruits T-cell help → memory; effective in infants where plain polysaccharide vaccines fail. Pittsburgh / Anderson 1980s pioneered.

  • Pneumococcal — Prevnar 13 (Pfizer; PCV13), Prevnar 20 (PCV20 2021), Vaxneuvance PCV15 (Merck), Capvaxive PCV21 (Merck 2024 adult-targeted serotypes).
  • Hib — ActHIB, Hiberix; eliminated invasive Hib disease.
  • Meningococcal A/C/W/Y — Menveo, Menactra, MenQuadfi (Sanofi 2020), Nimenrix.
  • Typhoid — Typbar TCV (Bharat Biotech), TYPHIBEV.

Viral vector

Recombinant adenovirus / poxvirus / measles / VSV expressing target antigen. Strong cellular + humoral immunity; pre-existing anti-vector immunity a constraint (drove ChAd6/ChAdOx1 chimp serotypes).

  • AdHu5 (human adenovirus 5) — high seroprevalence in adults; STEP HIV vaccine 2007 increased acquisition risk; partial deprecation for human-targeted use.
  • ChAd3, ChAdOx1 (Oxford simian Ad) — ChAdOx1 nCoV-19 / Vaxzevria (AstraZeneca-Oxford COVID); also ChAd3-Ebola (Sabue Mulangu trial in DRC).
  • Ad26.COV2.S (J&J / Janssen COVID; one-dose).
  • Sputnik V (Gamaleya; Ad26 prime / Ad5 boost; heterologous regime).
  • Ebola — rVSV-ZEBOV / Ervebo (Merck; licensed 2019, first Ebola vaccine).
  • Zabdeno + Mvabea (J&J; Ad26.ZEBOV + MVA-BN-Filo prime-boost; licensed EU 2020).
  • Mosquirix and modern mpox MVA-BN.

mRNA

LNP-encapsulated nucleoside-modified mRNA encoding antigen. Karikó-Weissman pseudouridine modification (Karikó, Weissman 2005 Immunity; Karikó 2008 Mol Ther) suppressed innate immune activation; 2023 Nobel Physiology/Medicine.

  • Comirnaty (BNT162b2; Pfizer-BioNTech; Şahin-Türeci) — ALC-0315 LNP from Acuitas Therapeutics.
  • Spikevax (mRNA-1273; Moderna; Bancel, Hoge, Zaks) — SM-102 LNP.
  • mRESVIA (mRNA-1345; Moderna RSV; approved May 2024).
  • CMV (mRNA-1647 Moderna; Phase 3 2024).
  • Seasonal flu — Moderna mRNA-1010 Phase 3 efficacy positive in 2024; Pfizer-BioNTech, GSK-CureVac in trials.
  • Combination flu+COVID (Moderna mRNA-1083; Pfizer-BioNTech).
  • Norovirus, HIV trimer (IAVI-Moderna), VZV, EBV, Lyme (Pfizer-Valneva — mRNA candidate distinct from VLA15 subunit).

Saponin adjuvants

Matrix-M (Novavax; saponin nanoparticles from Quillaja saponaria) used in NVX-CoV2373 and R21/Matrix-M malaria vaccine (Serum Institute / Oxford 2023 — higher efficacy than RTS,S, lower cost; WHO recommendation October 2023; Ghana and Nigeria first to license).

DNA vaccines

  • INO-4800 (Inovio COVID; electroporation delivery; modest efficacy).
  • ZyCoV-D (Zydus India; needle-free PharmaJet; first DNA COVID vaccine licensed in humans 2021).

Self-amplifying RNA (saRNA / replicon RNA)

Encodes both the antigen and an alphavirus-derived RNA-dependent RNA polymerase → in vivo amplification → lower dose required (microgram vs mRNA tens of micrograms).

  • Kostaive (ARCT-154; Arcturus + CSL; first saRNA vaccine licensed — Japan 2023).
  • GSK, CureVac, Replicate Bioscience, Sirnaomics, Gritstone bio active pipelines.

Virus-like particles (VLPs)

Self-assembling capsid-like structures lacking genome. Highly immunogenic.

  • HPV L1 VLP (Gardasil, Cervarix).
  • HepB surface antigen (Recombivax, Engerix — technically a VLP-like nanoparticle).
  • Mosquirix RTS,S/AS01 (GSK) — Plasmodium falciparum circumsporozoite protein fused to HBsAg VLP carrier + AS01 adjuvant. Pilot in Ghana, Kenya, Malawi 2019-2023 → WHO recommendation Oct 2021. Efficacy ~36% against clinical malaria; R21/Matrix-M is the lower-cost, higher-efficacy successor.
  • Cabotegravir long-acting injectable for HIV PrEP (not a vaccine but adjacent prophylactic; ViiV Apretude approved 2021).

Adjuvants

  • Alum (aluminum hydroxide / phosphate; Glenny 1926). Oldest licensed adjuvant; Th2-biased. NLRP3 inflammasome activation.
  • MF59 (Novartis / Seqirus; oil-in-water squalene; Fluad seasonal flu ≥65).
  • AS03 (GSK; squalene + α-tocopherol). Pandemrix H1N1 2009 — linked to narcolepsy in northern European children (Sami, Partinen 2012); caused major adjuvant safety reassessment.
  • AS01 (GSK; MPL monophosphoryl lipid A + QS-21 saponin in liposomes). Shingrix and RTS,S — landmark adjuvant.
  • CpG 1018 (Dynavax; TLR9 agonist). Heplisav-B; Corbevax (Biological E India RBD-CpG).
  • Matrix-M (Novavax; Quillaja saponin nanoparticle).
  • STING agonists, TLR4/7/8/9 agonist conjugates, α-galactosylceramide (NKT activator) — emerging.

Manufacturing platforms

  • Egg-based influenza — legacy; ~80% of seasonal flu supply; ~6-month lead time; egg-adaptation alters antigenicity (egg-passage mutations).
  • Cell-based — MDCK (Flucelvax), Vero (multiple), CHO. SK Bioscience SKYCovione (Vero-based COVID subunit).
  • Recombinant — Flublok (Sanofi; HA in Sf9 baculovirus / Spodoptera). Novavax NVX-CoV2373 (Sf9 baculovirus).
  • mRNA platform — IVT (in vitro transcription) of capped, polyadenylated, pseudouridine-modified mRNA; tangential flow filtration; in-line mixing with lipids (ionizable + helper + cholesterol + PEG-lipid) in microfluidic chips → LNP; downstream buffer exchange. ALC-0315 (Acuitas/Pfizer), SM-102 (Moderna), MC3 / DLin-MC3-DMA (Alnylam Onpattro).
  • Viral vector — cell line (HEK293, PER.C6 for Ad; AGE1.CR for MVA), bioreactor, downstream chromatography.
  • Plant-based — Medicago COVIFENZ (CoVLP) Canada-approved 2022, withdrawn 2024 after Mitsubishi shutdown.
  • Sterile fill-finish — cGMP under FDA 21 CFR 210/211 and EU GMP Annex 1 (revised 2023); cross-link design-pharma-fill-finish-line.

Selected vaccine impact

  • HPV. Lei, Ploner, Elfström 2020 NEJM — Swedish cohort showing 88% reduction invasive cervical cancer in vaccinated <17. Modeled 90% reduction long-term; Australia on track for cervical cancer elimination by ~2035; US adolescent coverage ~80%.
  • Rotavirus. Prevented ~500,000 child deaths per year globally since broad introduction.
  • Pneumococcal conjugate. Dramatic reduction in IPD invasive pneumococcal disease in vaccinated cohorts; herd effect.
  • MenB. Bexsero deployed UK 2015+ → meningococcal B disease reduction.

HIV vaccine — the persistent gap

  • STEP (Merck Ad5/gag/pol/nef 2007) — increased HIV acquisition in vaccinees with pre-existing Ad5 immunity; halted.
  • RV144 Thai trial (2009 NEJM; Rerks-Ngarm) — ALVAC-HIV + AIDSVAX gp120; modest 31% efficacy at 3 years; correlate IgG to V1V2.
  • HVTN 702 Imbokodo (2020-2021 failed in South African follow-on).
  • Mosaic + Trimer — Moderna IAVI mRNA HIV trimer (eOD-GT8 60mer germline-targeting; Schief Scripps) Phase 1-2 2022-23 elicits IgG bnAb-precursor responses in 97% of vaccinees (Leggat 2022 Science).

Cancer mRNA vaccines

Personalized neoantigen mRNA — patient tumor sequenced, neoantigens identified, custom mRNA encoding 30+ neoantigens manufactured and infused.

  • mRNA-4157 (V940) Moderna-Merck + Keytruda — Phase 2b KEYNOTE-942 melanoma adjuvant 44% recurrence reduction; Phase 3 INTerpath-001 reading out 2026-27.
  • BNT122 / autogene cevumeran BioNTech-Roche — pancreatic cancer Phase 2 underway; Phase 1 readout 2022 (Rojas, Balachandran Nature) — T-cell responses in ~50% of patients.

Surveillance + One Health

  • GISAID (Global Initiative on Sharing All Influenza Data; 2008; expanded to SARS-CoV-2, RSV, mpox).
  • Nextstrain (Bedford, Neher 2018 Bioinformatics) — phylodynamic real-time visualization.
  • Pango lineage (Rambaut 2020) — SARS-CoV-2 nomenclature (B.1.1.7 → Alpha, B.1.617.2 → Delta, BA.1+ → Omicron sublineages, JN.1, KP.3, XEC, current strain dominance shifts monthly).
  • WastewaterSCAN (Stanford / Emory) — population-level viral surveillance.

Major global health agencies

  • CEPI — Coalition for Epidemic Preparedness Innovations; founded 2017 Davos; >USD 1.5B funded for “100 Days Mission” to reach licensed vaccine within 100 days of new pathogen identification.
  • Gavi the Vaccine Alliance — ~USD 2B/yr disbursed for vaccine procurement in low/middle-income countries.
  • WHO + UNICEF Supply Division — vaccine procurement for ~40% of world children’s doses.
  • BARDA (US Biomedical Advanced Research and Development Authority) — Project NextGen successor to Operation Warp Speed; mucosal and pan-coronavirus vaccines.
  • IVI International Vaccine Institute Seoul.

Adjacent

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