AZD1222 (Vaxzevria)

Overview

AZD1222 was developed at the Jenner Institute, University of Oxford, and co-developed with AstraZeneca for large-scale manufacturing. Its first Emergency Use Listing from the WHO came on February 15, 2021, preceded by the UK MHRA (January 4, 2021) and EMA (January 29, 2021). It was never authorized by the FDA. The vaccine uses a replication-deficient chimpanzee adenovirus (ChAdOx1, derived from the Y25 strain) to deliver the SARS-CoV-2 spike gene. The use of a chimpanzee rather than human adenovirus serotype was deliberate: pre-existing immunity to ChAdOx1 is rare in humans, unlike human Ad5 (seroprevalence >50% in many populations), which would blunt immunogenicity.

The vaccine's defining logistical advantage — refrigerator stability at 2–8°C with a 6-month shelf life — made it the backbone of COVAX's 2021 rollout. The Serum Institute of India produced over 1.5 billion doses as Covishield, supplying the majority of low- and middle-income countries that received COVID-19 vaccines through multilateral mechanisms. Fiocruz (Brazil) and SK Bioscience (South Korea) handled regional supply chains.

In April–May 2021, post-authorization surveillance identified VITT (vaccine-induced immune thrombocytopenia and thrombosis) — a rare PF4-antibody-mediated syndrome causing thrombosis at unusual anatomical sites (cerebral venous sinus, portal/splanchnic veins) combined with thrombocytopenia. Occurring at approximately 1–3 per 100,000 doses, VITT prompted several European countries and Canada to restrict AZD1222 to older age groups, where the COVID-19 mortality risk outweighs the VITT hazard more clearly than in younger adults.

Platform & Antigen Design

ChAdOx1 Vector Architecture

  ChAdOx1 adenovirus backbone (Y25 chimpanzee adenovirus)
     E1 deletion ─── prevents replication in human cells
     E3 deletion ─── removes immune evasion genes / creates insert space
          │
          └─ Transgene: full-length SARS-CoV-2 spike
               CMV promoter (ubiquitous high-level expression)
               tPA leader sequence (efficient surface secretion)
               No prefusion-stabilizing 2P mutations

  IM injection → ChAdOx1 infects muscle cells + APCs at injection site
          │
          ├─ Spike mRNA transcribed → spike expressed on cell surface
          │
          ├─ Adenovirus PAMPs → TLR2/4/9 → NF-κB → DC maturation
          │    (intrinsic adjuvanting; no exogenous adjuvant required)
          │
          ├─ DCs → draining lymph node
          │    MHC II: spike peptides → CD4⁺ Th1 priming
          │    MHC I:  spike peptides → CD8⁺ CTL priming (cytoplasmic delivery)
          │
          └─ Germinal center → anti-spike IgG + memory B cells + memory T cells

1. Vector entry: ChAdOx1 enters cells via CAR/CD46 receptors; rare pre-existing immunity ensures efficient infection and antigen expression before immune clearance.
2. Spike transcription: CMV promoter drives immediate high-level spike mRNA production; tPA signal peptide boosts surface display and extracellular secretion for B-cell receptor engagement.
3. Innate activation: Adenovirus capsid proteins activate TLR2, TLR4, and TLR9 — producing DC maturation signals (IL-12, IFN-β, TNF-α) that amplify adaptive immune responses without exogenous adjuvant.
4. MHC I loading: Cytoplasmic spike peptides load MHC I molecules on infected cells, priming CD8&sup+ cytotoxic T lymphocytes — a key advantage over protein subunit vaccines.
5. Dose interval effect: 8–12 week spacing between doses markedly increases antibody titers and T-cell responses vs. 4-week interval, via longer germinal center maturation and higher-affinity B-cell selection.

Immunogenicity

Clinical Efficacy

Safety Profile

• Very Common Injection-site pain, fatigue, headache, myalgia — >60–80% of vaccinees; onset day 1–2; resolves within 1–3 days. More pronounced after dose 1 than dose 2 (reverse of mRNA vaccines). Prophylactic paracetamol reduces reactogenicity.
• Common Low-grade fever (37.5–38.5°C) — 20–30%; day 1–2; self-limiting. Uncommon severe systemic reactions (<1%): grade 3 fever, chills, rigors.
• Rare / Serious VITT (Vaccine-Induced Immune Thrombocytopenia and Thrombosis) — ~1–3 per 100,000 doses; onset 4–28 days post-dose 1; unusual thrombosis (CVST, portal/splanchnic vein) + thrombocytopenia. Mechanism: PF4-reactive IgG activates platelets via FcγRIIa — heparin-independent HIT mimic. Treatment: IVIG + non-heparin anticoagulants (argatroban, danaparoid); avoid heparin. Case fatality ~20–25%; absolute risk ~1/500,000 doses in confirmed cases.
• Uncommon Capillary leak syndrome — very rare post-marketing reports; outcome variable; under active surveillance.
• Very Rare Anaphylaxis — rare hypersensitivity reactions; standard 15-minute observation period post-injection; manageable with epinephrine.

Administration

Connections

References

• Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020;396(10249):467-478. doi:10.1016/S0140-6736(20)31604-4 · PMID 32702298
• Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99-111. doi:10.1016/S0140-6736(20)32661-1 · PMID 33306989
• Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021;384(22):2092-2101. doi:10.1056/NEJMoa2104840 · PMID 33835769
• Sheikh A, McMenamin J, Taylor B, Robertson C; Public Health Scotland and the EAVE II Collaborators. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet. 2021;397(10293):2461-2462. doi:10.1016/S0140-6736(21)01358-1 · PMID 34139198
• Knoll MD, Wonodi C. Oxford–AstraZeneca COVID-19 vaccine efficacy. Lancet. 2021;397(10269):72-74. doi:10.1016/S0140-6736(20)32623-4 · PMID 33306990