Active immunisation: how vaccines generate protection

At a glance

• Active immunisation presents antigen so the host makes its own antibody and memory. Protection takes 1 to 2 weeks to start and lasts years. Passive immunisation (ready-made antibody) is in passive immunisation.
• Protein antigens are T-dependent: they give class switching, affinity maturation and memory. Pure polysaccharides are T-independent: short-lived IgM-dominant responses, none under age 2.
• Live vaccines replicate, so they give broad, durable immunity after one or two doses, but are contraindicated in pregnancy and significant immunosuppression.
• Most vaccines protect through neutralising antibody. Zoster and BCG rely mainly on T cells.

How a vaccine builds immunity

1. Innate trigger. Adjuvants or the pathogen's own molecules activate dendritic cells through pattern recognition receptors. Aluminium salts form a depot and activate the inflammasome. AS01 (Shingrix, Arexvy) contains MPL (a TLR4 agonist) and QS-21 saponin and drives strong CD4 T cell responses, which is why it overcomes immunosenescence. See innate immunity and pattern recognition.
2. Priming. Dendritic cells carry antigen to lymph nodes and present it to naive CD4 (and for live and mRNA vaccines, CD8) T cells.
3. Germinal centre. T follicular helper cells drive B cell class switching to IgG, somatic hypermutation and selection for high affinity. Output: long-lived plasma cells in bone marrow and memory B cells.
4. Boosting. Re-exposure activates memory B cells within days, giving a faster, higher, higher-affinity IgG response.

Primary versus secondary response

	Primary	Secondary (booster)
Lag	7 to 14 days	3 to 5 days
Main isotype	IgM then IgG	IgG
Peak titre	Low	10 to 100 times higher
Affinity	Low	High (matured)

The minimum interval between primary doses (usually 4 weeks) lets the germinal centre reaction settle. Doses given too close together count less. A delayed dose never needs the course restarted.

Vaccine types

Type	Examples	Immune features	Practical points
Live attenuated	MMR, varicella, yellow fever, oral rotavirus, BCG	Replicates; antibody plus CD8 T cells; often lifelong	Avoid in pregnancy and significant immunosuppression; separate from another live parenteral vaccine by 4 weeks if not same day
Inactivated whole	Hepatitis A, IPV, rabies, Q fever	Antibody, needs boosters	Q fever needs pre-testing (skin and serology) to avoid severe local reactions
Subunit or recombinant protein	Hepatitis B, HPV (virus-like particle), Shingrix, Arexvy and Abrysvo (RSV prefusion F)	T-dependent, adjuvant often needed	Safe in immunocompromise
Toxoid	Tetanus, diphtheria	Antitoxin IgG	Protection is purely antibody; disease does not give immunity
Polysaccharide	23vPPV, typhoid Vi	T-independent, no memory, possible hyporesponsiveness with repeat doses	Poor under age 2
Conjugate	Pneumococcal conjugate, Hib, MenACWY, MenC	T-dependent via carrier protein; reduces nasopharyngeal carriage, so herd effect	Responses from 6 weeks of age
mRNA	COVID-19	Lipid nanoparticle delivers mRNA; host cells make spike; antibody plus CD8 T cells	Myocarditis risk highest in young males after dose 2

Conjugate vaccines cut carriage, which gives indirect protection to unvaccinated adults. That is why adult invasive Hib disease almost disappeared after infant vaccination.

Worked examples

Vaccine efficacy. In a trial, influenza occurs in 60 of 1,000 unvaccinated and 24 of 1,000 vaccinated people.

• Relative risk = 0.024 / 0.060 = 0.40
• VE = 1 minus 0.40 = 60%
• Absolute risk reduction = 6.0% minus 2.4% = 3.6%, so NNV = 1 / 0.036 = 28

The same VE gives a much smaller NNV in a high-incidence season. See absolute and relative risk.

Herd immunity. Threshold = 1 minus 1/R0. Measles (R0 12 to 18) needs 92 to 94% immune. Because 2 doses of MMR are about 97% effective, required coverage = 0.93 / 0.97 = about 96%. Influenza (R0 about 1.5) needs only 33%, but low efficacy and antigenic drift undo that.

Correlate of protection. Anti-HBs of 10 mIU/mL or more after the course means lifelong protection in immunocompetent people, even if titres later fall below 10, because memory persists. About 5 to 10% of healthy adults are non-responders (older age, obesity, smoking, CKD, HLA-DRB1 types). If anti-HBs is under 10 mIU/mL after the primary course, give a single booster (4th) dose and retest 4 weeks later. Still under 10 confirms non-response: test for infection (HBsAg, anti-HBc), then give 2 more doses 1 month apart, counting the booster as the first dose of the repeat course, and retest at least 4 weeks after the last dose. The Handbook finds no consistent evidence that high-dose or double-dose regimens work better. Persistent non-responders need HBIG within 72 hours of any exposure. See viral hepatitis.

Current Australian points that are examined

• Shingrix (2 doses, 2 to 6 months apart; 1 to 2 months if immunocompromised) is NIP funded from 65, from 50 for Aboriginal and Torres Strait Islander people, and from 18 for specified immunocompromising conditions. See varicella zoster virus.
• RSV: Abrysvo is NIP funded as a single dose from 28 weeks, ideally by the end of 36 weeks, and as soon as possible if missed. The Handbook (updated May 2026) recommends it in each pregnancy, although evidence for repeat doses is limited and federal program advice says repeat-dose advice will follow. If birth occurs less than 2 weeks after the maternal dose, the infant should get nirsevimab. Arexvy is funded from 15 May 2026 as a single dose for adults 75 and over and Aboriginal and Torres Strait Islander adults 60 and over.
• Pregnancy: dTpa (ideally 20 to 32 weeks) and influenza (any trimester) protect the infant by transplacental IgG, which crosses via FcRn mainly in the third trimester. Live vaccines are avoided.
• Immunocompromised hosts are covered in immunisation in the immunocompromised host.

How it's tested

• Why a polysaccharide vaccine fails in infants or asplenic patients, and why conjugates work.
• Calculating VE, NNV or herd immunity thresholds.
• Interpreting post-vaccine serology (anti-HBs, varicella IgG).
• Contraindications to live vaccines and timing intervals.
• Vaccines whose protection is T cell mediated (zoster), so antibody testing is unhelpful.

Pitfalls

• An interrupted course is continued, not restarted.
• Tetanus and diphtheria infection do not confer immunity; vaccinate after recovery.
• Anti-HBs below 10 years after a documented response is not an indication for revaccination in an immunocompetent person.
• Recent immunoglobulin or blood products blunt live parenteral vaccines (MMR, varicella), but not inactivated vaccines or oral rotavirus.
• Repeated 23vPPV doses can cause hyporesponsiveness, so follow the Handbook schedule rather than giving extra doses.