Vaccines & Antivirals

1. Vaccine Platforms

• Live attenuated — weakened virus that replicates without causing disease. Examples: MMR (measles, mumps, rubella), oral poliovirus (OPV/Sabin), yellow fever 17D, varicella, rotavirus. Strong durable immunity, but not for the immunocompromised.
• Inactivated — killed virus, formalin or β-propiolactone. Salk polio (IPV), influenza, hepatitis A, rabies. Safe but typically requires boosters and adjuvants.
• Subunit / recombinant protein — purified protein antigen, often with adjuvant. Hepatitis B (recombinant HBsAg), HPV (L1 VLPs), Shingrix (recombinant gE + AS01 adjuvant). Excellent safety; tunable.
• Polysaccharide-conjugate — capsular polysaccharide chemically conjugated to a carrier protein. PCV13/PCV20 (pneumococcus), Hib, MenACWY.
• Viral-vector — replication-incompetent (or replication-defective) virus carrying the antigen gene. ChAdOx1 (AstraZeneca COVID-19), Ad26 (J&J), rVSV-ZEBOV (Ebola).
• mRNA — synthetic, modified mRNA encoding the antigen, in lipid nanoparticles. Pfizer/BioNTech and Moderna COVID-19 vaccines (BNT162b2, mRNA-1273); Kariko & Weissman 2023 Nobel for the pseudouridine modification that solved the mRNA immunogenicity problem.
• DNA — plasmid DNA injection; one approved animal vaccine; human use limited. Self-amplifying mRNA is the active research frontier.

2. The mRNA Revolution

The COVID-19 mRNA vaccines were designed in days, manufactured at billion-dose scale within a year, and gave 95% protection against severe disease. The key innovations:

• Pseudouridine substitution (Kariko & Weissman 2005) reduced TLR-mediated inflammation and increased translation 10×.
• Cap-1 5′-cap analogue for efficient translation initiation.
• Lipid nanoparticles (LNPs): ionisable lipids that protonate at endosomal pH, escape the endosome, and deliver mRNA to the cytoplasm.
• Pre-fusion stabilisation of the spike protein (2P mutations, pioneered by McLellan, Graham & Corbett for RSV F and adapted to SARS-CoV-2).

mRNA platforms are now being applied to RSV, influenza, CMV, HIV, malaria, and cancer neoantigen vaccines. The platform decouples antigen design from manufacturing — sequence in, vaccine out.

3. Antiviral Drug Targets

• Entry inhibitors — maraviroc (CCR5 antagonist for HIV), enfuvirtide (gp41 fusion peptide), bulevirtide (HBV NTCP entry).
• Polymerase inhibitors — nucleoside analogues (acyclovir for herpes; sofosbuvir for HCV; remdesivir, molnupiravir for SARS-CoV-2; tenofovir for HBV/HIV); non-nucleoside (efavirenz for HIV).
• Protease inhibitors — lopinavir/ritonavir, darunavir for HIV; nirmatrelvir/Paxlovid for SARS-CoV-2.
• Integrase inhibitors — raltegravir, dolutegravir, bictegravir; the backbone of modern HIV combination therapy.
• Neuraminidase inhibitors — oseltamivir (Tamiflu), zanamivir, baloxavir (cap-snatching endonuclease) for influenza.
• Capsid inhibitors — lenacapavir for HIV, the first long-acting (6-monthly) injectable antiretroviral.
• Monoclonal antibodies — palivizumab for RSV in infants; bamlanivimab and others for COVID-19 (largely escaped by Omicron); Inmazeb and Ebanga for Ebola.

4. Resistance and Combination Therapy

Single-drug treatment of an actively replicating virus selects for resistance within days (HIV) or weeks (HBV, HCV before direct-acting antivirals). The solution is combination therapy: simultaneous inhibition of multiple steps means resistance requires multiple mutations — statistically vanishing. cART for HIV uses 3 drugs from 2 classes; HCV uses 2 direct-acting antivirals from 2 classes; multi-drug regimens for HBV remain an open question because cccDNA is not eliminable. Pan-resistance to oseltamivir in seasonal H1N1 (2007–2008) showed how rapidly a single-drug strategy can collapse.

5. Universal Vaccines & the Frontier

The frontiers: a universal influenza vaccinetargeting the conserved HA stalk; an HIV vaccine that elicits broadly neutralising antibodies targeting the gp41 MPER and CD4-binding-site epitopes; a pan-coronavirus vaccine; therapeutic vaccines that induce CD8 responses against chronic infections (HBV, HSV); and the long-pursued goal of an HIV cure — either by eliminating the latent reservoir (“shock and kill”) or by inducing durable control without ART (functional cure). Stem-cell transplants from CCR5-Δ32 donors have produced a small number of confirmed cures (Berlin patient, London patient).