mRNA vaccines for infectious diseases: principles, delivery and clinical translation

Purpose: mRNA vaccines have progressed from a scepticism-inducing idea to clinical reality, with COVID-19 catalysing the fastest vaccine development in history. Remaining needs include optimizing mRNA design, intracellular delivery, and applications beyond SARS-CoV-2 prophylaxis. This review describes mRNA vaccine technologies, with emphasis on lipid nanoparticles and other non-viral delivery vehicles.

Hypothesis: No formal experimental hypothesis. Central thesis: synthetic mRNA, when optimized and packaged in effective non-viral delivery vehicles—especially lipid nanoparticles—can rapidly and safely elicit protective immunity against infectious diseases, but further optimization is needed for broad translation.

Aims: Describe the technical basis of mRNA vaccines: mRNA design, synthesis, and delivery technologies. - Emphasize lipid nanoparticles and other non-viral delivery vehicles. - Overview the pipeline of mRNA vaccines against various infectious disease pathogens. - Discuss key future questions: safety, duration of response, specific populations, and global vaccine access.

Delivery system: mRNA type: in vitro-transcribed (IVT) mRNA or self-amplifying mRNA; five structural elements: 5′ cap, 5′ UTR, open reading frame, 3′ UTR, poly(A) tail; modifications include N1-methylpseudouridine, pseudouridine, codon optimization, CleanCap, HPLC purification, and encoded poly(A) tails. - Lipid nanoparticles (LNPs): ionizable lipid (e.g., DLin-MC3-DMA, SM-102, ALC-0315, A18-Iso5-2DC18, A6, 306O10), cholesterol or variants (β-sitosterol, 20α-hydroxycholesterol), helper lipid (DSPC, DOPE), PEGylated lipid (PEG-DMG, ALC-0159). - Other vehicles: polymeric nanoparticles (PEI, PBAE, PEG-PAsp(DET), CART), cationic nanoemulsions (squalene, DOTAP, Tween 80, Span 85), peptides (RALA, PepFect14, protamine). - Payloads: mRNA encoding antigens (SARS-CoV-2 spike, influenza haemagglutinin, Zika prM-E, RSV F protein, Ebola/rabies glycoproteins, PMIF, PfGARP) or monoclonal antibodies (ZIKV-117, CHKV-24, VRC01). - Route/targeting: intramuscular, intradermal, subcutaneous; targeting immune cells, T cells, dendritic cells, macrophages.

Approach: Review of preclinical and clinical literature. Clinical trials span phase I–III for SARS-CoV-2, influenza, Zika, RSV, CMV, chikungunya, and rabies, with participant numbers from small phase I studies up to 43,998 (BNT162b2) and 30,420 (mRNA-1273). Preclinical models include mice, ferrets, rabbits, pigs, guinea pigs, rhesus macaques, and Aotus monkeys. Doses range from nanograms to 400 µg; controls include convalescent serum, licensed vaccines, and placebo.

Key methods: Clinical efficacy: prevention of symptomatic COVID-19, hospitalization, and severe disease; real-world effectiveness. - Immunogenicity: neutralizing antibody titres, anti-spike/RBD IgG, serum neutralization, CD4⁺/CD8⁺ T cell responses, germinal centre B cells, T follicular helper cells. - Safety: local/systemic adverse events, anaphylaxis rates, anti-PEG antibodies. - Preclinical: viral challenge protection, LD50, mucosal IgG/IgA, biodistribution. - LNP characterization: size, dispersity, encapsulation efficiency, pKa, surface charge, haemolytic activity; microfluidic formulation parameters.

Key results: BNT162b2: 95% overall efficacy in phase III (43,548 participants); real-world Israel data: 94% against symptomatic COVID-19, 87% against hospitalization, 92% against severe disease; 90–100% efficacy across subgroups. - mRNA-1273: 94.1% efficacy in phase III (30,420 volunteers); real-world two-dose effectiveness 90%; 86.4% efficacy in ≥65 years vs 95.6% in 18–65 years. - CVnCoV: 47% efficacy in phase IIb/III (40,000 participants); 57% of sequenced cases were variants of concern. - Preclinical: two 100 µg BNT162b2 doses in macaques elicited neutralizing antibody titres 10.2–18.0× convalescent serum; mRNA-1273 in macaques gave 15× higher neutralizing titres, 348× ACE2-binding inhibition, and 12× virus-neutralizing activity versus convalescent serum. A 50 ng influenza mRNA vaccine protected mice against 500× LD50.

Interpretation: mRNA vaccines have validated the platform and elevated LNPs and RNA therapy from niche products to broadly deployed prophylactic medicines. The authors are optimistic that mRNA therapeutics will transform vaccination, cancer immunotherapy, protein replacement therapy, and beyond.

Limitations: Review article; no primary data. - Written as of June 2021; predates Omicron and later variants/boosters. - Cold-chain storage remains a logistical barrier (BNT162b2 requires −60°C; mRNA-1273 can be stored at 4–8°C for 1 month). - Rare anaphylaxis observed (~4.7 per million Pfizer, 2.5 per million Moderna); anti-PEG antibodies in ~40% of the population may affect efficacy/safety. - Duration of antibody response and long-term safety in pregnancy, elderly, and paediatric populations need more data. - Global access and vaccine acceptance remain major challenges.