Viral Vaccines — Questions

The major capsid protein L1 self-assembles into virus-like particles (VLPs) that mimic the capsid surface and raise neutralising antibody while containing no viral DNA. This is the molecular basis of the prophylactic HPV vaccines.

L2 is the minor capsid protein; E6 and E7 are the oncoproteins; E2 controls viral transcription.

The recombinant glycoprotein E subunit vaccine with the AS01B adjuvant, given as two doses, has superseded the older live-attenuated zoster vaccine. It gives high, durable protection of around 90% that does not wane with age, and because it is non-live it is safe in the immunocompromised, the group at greatest need.

The childhood varicella vaccine prevents primary chickenpox, and immunoglobulin is for post-exposure prophylaxis, neither being active immunisation against zoster.

Measles vaccines (measles-rubella [MR], measles-mumps-rubella [MMR], and measles-mumps-rubella-varicella [MMRV]) contain live attenuated virus that must replicate in the recipient to provoke immunity. About 5 to 15% of vaccinees develop a mild, transient maculopapular rash 5 to 12 days after vaccination, often with low-grade fever. This is the expected immune response to vaccine-strain replication: the same immunopathology as wild-type measles, markedly attenuated.

The reaction is not a hypersensitivity to excipients, not contamination, and not reactivation of a latent virus, and it is not driven by maternal antibody. Where serology is positive and the clinical picture is ambiguous, a vaccine-associated reaction is distinguished from breakthrough wild-type infection by genotyping (the vaccine strain is genotype A) at a reference laboratory, and by a low immunoglobulin M (IgM) to immunoglobulin G (IgG) ratio compared with primary wild-type infection.

• Lifelong latency in sensory neurons that are poorly accessible to immune surveillance, so a vaccine cannot easily prevent or clear established infection.
• Sophisticated immune evasion and the absence of a validated correlate of protective immunity to guide vaccine design.
• No suitable animal model that faithfully reproduces human infection, latency and recurrence; the leading glycoprotein D subunit candidate failed against HSV-2 in trials.

Structure drives immunogenicity. A VLP is built from viral capsid proteins that self-assemble into a particle with no genome. Displaying the proteins on a regular, repetitive, native-shaped surface cross-links B cell receptors strongly, so VLPs are far more immunogenic than the equivalent free protein.

Quality of response. Because the epitopes are in their folded conformation, the antibodies raised are neutralising and durable; the HPV vaccine gives protection lasting well over a decade.

Safety. Containing no nucleic acid, a VLP cannot replicate, infect or revert, and needs no chemical inactivation that might damage epitopes, so it is safe in pregnancy and immunocompromise.

Caveats. A purified particle still usually needs an adjuvant, manufacture is complex and costly, and there is no antigen amplification after injection. The hepatitis B and HPV vaccines are the licensed examples.

Nature. Both are monoclonal antibodies against the respiratory syncytial virus (RSV) fusion (F) protein, giving passive protection. Palivizumab is given monthly through the RSV season; nirsevimab is engineered for a long half-life, so a single dose covers a whole season.

Indications. Prevention, not treatment, of severe RSV lower-respiratory-tract disease in infants: palivizumab for high-risk infants (prematurity, chronic lung disease, significant congenital heart disease), and nirsevimab for a broader infant population. Neither helps once RSV infection is established.

Strain selection. Twice a year the World Health Organization reviews surveillance data and recommends the strains for the coming season.

Egg-based production. The vaccine virus is grown in embryonated hen eggs. Because wild strains often grow poorly, a high-yield reassortant is made by combining the surface genes (haemagglutinin and neuraminidase) of the recommended strain with the internal genes of a laboratory strain that grows well in eggs. The harvested virus is then inactivated and, for most products, split.

The problem. Growth in eggs is slow, limiting how quickly the vaccine can be updated, and the virus can acquire egg-adaptation mutations in haemagglutinin that change the antigen so the vaccine matches the circulating strain less well. Cell-based and recombinant production avoid egg adaptation.

• Severe combined immunodeficiency (SCID): a live vaccine can cause prolonged or disseminated infection.
• Previous intussusception, or an uncorrected congenital gastrointestinal malformation predisposing to it.
• Severe hypersensitivity to a previous dose or to a vaccine component.
• Outside the age window: the course must not be started or completed late (no dose after 24 weeks of age), a timing restriction rather than a true contraindication but applied strictly.

• IgG: a single Y-shaped monomer; the main serum antibody, neutralising virus and crossing the placenta, and the basis of most passive immunisation.
• IgM: a large pentamer; the first antibody of a primary response and a marker of recent or acute infection.
• IgA: a monomer in blood but a dimer in secretions; the secretory antibody at mucosal surfaces and in breast milk, the key mucosal defence.
• IgE: a single Y-shaped monomer; allergy and antiparasite responses, with only a minor antiviral role.
• IgD: a single Y-shaped monomer; largely a B-cell surface receptor, with little defined antiviral effector role.

• (a) False. Inactivated influenza vaccine is recommended, not contraindicated, in pregnancy and in HIV at any CD4 count; it is non-live and safe, and both pregnancy and HIV raise the risk of severe influenza.
• (b) True. HPV vaccination is recommended for HIV-infected people regardless of CD4 count, ART use or viral load, including men who have sex with men up to about 40 years, because of their high HPV-associated cancer risk.
• (c) True. Hepatitis A vaccine is inactivated and safe in HIV; the standard two-dose schedule is appropriate, and chronic liver disease is itself an indication. Checking post-vaccination antibody is reasonable, as the response may be reduced.
• (d) False. The varicella vaccine is live and contraindicated at a CD4 count of 150 cells/uL. Give varicella-zoster immunoglobulin (VZIG) for post-exposure prophylaxis instead.

• Pfizer-BioNTech COVID-19 vaccine (Comirnaty): mRNA vaccine in a lipid nanoparticle, encoding the pre-fusion spike protein.
• Cervarix: virus-like particle (HPV L1) vaccine, bivalent (types 16 and 18), with the AS04 adjuvant.
• Annual inactivated influenza vaccine: inactivated (killed) vaccine, usually split or subunit, grown in eggs or cell culture.
• Mumps vaccine: live attenuated vaccine (the Jeryl Lynn strain), given within MMR.
• Shingrix: recombinant protein subunit vaccine (varicella-zoster glycoprotein E) with the AS01B adjuvant.

Nature. A cold-adapted, live attenuated influenza vaccine given intranasally. The vaccine strains replicate at the cooler temperature of the nose but not in the warmer lower respiratory tract, so they induce local immunity without causing disease.

Advantage. Being live and mucosal, it raises secretory IgA at the portal of entry and a broad response, and the needle-free route suits children.

Composition. Reformulated each year by reassortment to carry the recommended seasonal haemagglutinin and neuraminidase on the cold-adapted backbone.

Limitations. As a live vaccine it is contraindicated in pregnancy and in immunocompromise, and it is used in a defined age range rather than across all groups; inactivated vaccine is used where a live product is unsuitable.

Principle. An mRNA vaccine delivers messenger RNA encoding a viral antigen, usually a surface protein, inside a lipid nanoparticle. The host cell translates the RNA and makes the antigen itself, so immunity resembles that from a live vaccine, including CD8 T cell responses, without any infectious agent.

Key enabling advances. Substituting uridine with pseudouridine reduces innate recognition of the RNA and raises protein output, and the lipid nanoparticle both protects the RNA and acts as an adjuvant. Encoding the antigen in its pre-fusion shape improves the quality of neutralising antibody.

Advantages. Designed from sequence alone, so very fast to develop (the first COVID-19 vaccine was authorised in under eleven months); no need to culture the virus; readily updated for a drifting or pandemic strain.

Disadvantages. Short antibody durability requiring boosters; a demanding cold chain; and greater reactogenicity than older vaccines.

Examples. The COVID-19 vaccines Spikevax and Comirnaty; influenza, cytomegalovirus and respiratory syncytial virus mRNA vaccines are in development.

A complete answer first checks existing immunity, then separates live from inactivated vaccines and sequences the doses within the time available.

Assessment first. Take a vaccination history and, where useful, check serology (measles, rubella, varicella, hepatitis B). Do a pregnancy test: the live vaccines (MMR and varicella) are contraindicated in pregnancy, and pregnancy should be avoided for one month after them.

Live vaccines (give on the same day, or at least 4 weeks apart).

• MMR: one or two doses depending on documented immunity.
• Varicella: two doses 4 to 8 weeks apart if there is no history or evidence of immunity.

Inactivated vaccines (flexible timing, may be co-administered at separate sites).

• Hepatitis A: two doses at 0 and 6 to 12 months.
• Hepatitis B: three doses at 0, 1 and 6 months (an accelerated 0, 7, 21 days plus a 12-month dose if time is short). Combined hepatitis A and B is an option.
• Typhoid: single-dose Vi polysaccharide (inactivated).
• Polio: an inactivated polio (IPV) booster.
• dTaP: a single adult Tdap dose, reviewing tetanus and diphtheria status.

A workable sequence. Day 0: MMR, varicella (1), hepatitis A (1), hepatitis B (1), IPV, Tdap and typhoid together at separate sites. Then varicella (2) at 4 to 8 weeks; hepatitis B (2) at 1 month and (3) at 6 months; hepatitis A (2) at 6 to 12 months. Document everything for the destination country’s entry requirements.

The defensible recommendation is the hepatitis B virus (HBV) birth dose, which South Africa subsequently adopted into the EPI in April 2020. The case rests on prioritising by disease burden, intervention efficacy, cost-effectiveness and the programmatic gap.

Disease burden favours HBV. HBV prevalence is ~6.7% in the general population and higher in HIV, and genotype A1 confers a roughly four-fold HCC risk in young Black men with early onset; hepatocellular carcinoma is a leading cancer death in this group. Vertical transmission is the principal route of chronic acquisition, with ~90% of perinatally infected infants becoming chronic and a quarter to 40% dying of cirrhosis or HCC. By contrast, primary varicella is largely self-limiting in healthy children, with severe disease concentrated in the immunocompromised.

The birth dose closes a window no other intervention covers. HBV is acquired at delivery and chronicity established within days, so the first hexavalent dose at 6 weeks is too late; only a dose within 24 hours interrupts it. A VZV programme would largely substitute for natural exposure most children already encounter.

Cost-effectiveness strongly favours HBV. The monovalent dose costs ~USD 0.20 and prevents decades of life lost, against ~USD 50 for VZV vaccine preventing a self-limiting illness. It is co-administrable with BCG and OPV already given at birth, minimising added cost.

International endorsement and a real gap. The WHO has recommended a universal birth dose since 2009, and Taiwan’s universal infant programme cut childhood HBsAg prevalence from 9.3% to 0.5% with sharp falls in childhood HCC. Until 2020 South Africa had no systematic perinatal HBV prevention, so the birth dose plus universal antenatal screening closes the major gap.

VZV vaccine would take priority only where HBV burden was low and already controlled, a universal birth dose was in place, and childhood varicella morbidity was high enough to justify a two-dose live-vaccine programme.

A complete answer gives the rationale, the vaccine and its evidence, the alternative passive approach, and the caveats.

Rationale. RSV causes its most severe disease in the first months of life, before an infant can mount a good vaccine response. Maternal IgG crosses the placenta, so immunising the mother in pregnancy delivers protective antibody to the newborn at exactly the vulnerable time.

The vaccine. A recombinant pre-fusion F protein vaccine given in pregnancy (around 28 to 36 weeks) raises maternal neutralising antibody that is transferred to the fetus.

Evidence. Maternal vaccination reduces severe RSV lower-respiratory-tract disease in the first months of life.

The alternative. A long-acting monoclonal antibody given to the infant (nirsevimab) provides the same protection passively and directly, and is an option where maternal vaccination is not used.

Caveats. The timing window matters for adequate antibody transfer, preterm infants may receive less, and safety in pregnancy and around gestational age has been a focus of evaluation.

A complete answer lists the priority groups, gives the rationale, and critiques the strategy.

Priority groups. Pregnant women; people living with HIV; those with chronic cardiac, pulmonary, renal or metabolic disease; the elderly; and healthcare workers. The very young are also at higher risk.

Rationale. The inactivated vaccine is safe in pregnancy and in HIV, and reduces severe disease and complications in exactly these higher-risk groups, where influenza adds to an already heavy respiratory and HIV/TB burden.

Critique. Influenza vaccine sits outside the routine EPI, so delivery and coverage are limited; the egg-based vaccine can mismatch the circulating strain; and annual reformulation and re-vaccination are needed. In a resource-constrained system a targeted risk-group strategy, rather than universal vaccination, is the appropriate use of limited doses, though cell-based and mRNA vaccines may improve the match in future.

The two parallel SA vaccines

The two are pharmacologically similar live-attenuated products with a shared adverse-event profile.

Contraindications

The clinically important contraindications (both vaccines):

• Pregnancy — and planning pregnancy within 3 months; pregnancy should be avoided for 1 month after vaccination. Live attenuated vaccines.
• Severe immunosuppression — congenital immunodeficiency, haematological malignancy on treatment, post-transplant immunosuppression, high-dose corticosteroids (≥2 mg/kg/day or ≥20 mg/day prednisone-equivalent for ≥2 weeks) or other potent immunosuppressives, or HIV with low CD4 (<15% if ≤5 yr; <15% and count <200/µL if >5 yr).
• Severe allergic reaction to a previous dose, or known anaphylaxis to vaccine components — notably neomycin or gelatin.

Precautions and risk groups

• Defer for systemic illness with temperature >38.5 °C; minor illness is not a contraindication.
• HIV-infected children — safe unless severely immunocompromised (above thresholds); no increased risk of serious adverse events.
• Neurological disorders / epilepsy / family history of febrile seizures — benefits outweigh risks, but counsel on the known increased risk of febrile seizures after vaccination.
• Egg allergy — safe; residual ovalbumin is minimal. (The older “egg allergy is a contraindication” teaching is out of date.)
• Health-care workers — especially important to vaccinate, given documented outbreaks in healthcare settings.
• MMRV is contraindicated in HIV regardless of CD4 — use MMR.
• Recent immunoglobulin or blood products — defer 3–11 months depending on product (passive antibody neutralises the live vaccine).
• Personal history of ITP — small risk of recurrence; weigh against measles risk.

Adverse events

Mostly mild: injection-site reactions, low-grade fever, transient rash. Less common: febrile seizures (especially after the first dose), arthralgia, transient thrombocytopaenia. Rare: anaphylaxis, encephalitis.

Post-exposure prophylaxis

Per the NICD framework (Prevention of secondary cases, 2022). PEP goes to any contact without documented immunity who was exposed during the index case’s infectious period (4 days before to 4 days after rash).

(i) Immunocompetent child. Measles-containing vaccine within 72 hours of exposure — MR (Cipla) in the public sector, MMR in the private. Still worth giving after 72 hours (safe in someone already incubating; boosts the already-immune). For infants 6–8 months, the PEP dose does not replace the routine schedule. Infants <6 months are too young for live vaccine and need NHIG if the mother is non-immune. Effectiveness (NEJM 2025 meta-analysis): 83–100%.

(ii) Immunocompromised contact (or vaccine-contraindicated). Normal human immunoglobulin (NHIG) 0.5 mL/kg IM (max 15 mL) within 6 days. Candidates: severe primary immunodeficiency, haematological malignancy on chemotherapy, HSCT/SOT recipients on immunosuppression, HIV with CD4 below thresholds above, infants <6 months whose mothers are non-immune, pregnant women without evidence of immunity. Caveat: the measles-neutralising antibody content of contemporary NHIG has declined (donors are increasingly vaccine- rather than naturally-immune) — efficacy is uncertain and the recommended dose is under review. Effectiveness: 76–100%, with greater short-term protection than vaccine but greater cost and limited LMIC availability. For HIV-infected contacts, the NICD recommends vaccine within 72 h if CD4 is adequate, NHIG otherwise.

In all cases, notify the NICD — measles is a Category 1 NMC.

Primary vs secondary vaccine failure

Primary vaccine failure — failure to seroconvert after vaccination. About 10–15% of infants given the first dose at 9 months fail to seroconvert (lower with later dosing). Main contributors:

• Maternal-antibody interference — passively-acquired IgG neutralises live vaccine virus in young infants (the reason elimination-status countries delay the first dose to 12–18 months).
• Younger age at vaccination — lower immunogenicity.
• Host immune compromise at the time of vaccination (HIV with low CD4, congenital immunodeficiency, immunosuppressive therapy).
• Cold-chain failure — measles vaccine is live and heat-labile.
• Moderate-to-severe acute illness at vaccination.

Secondary vaccine failure — waning immunity in someone who did initially respond. Vaccine-induced antibody levels are lower than those from natural infection, and without boosting from circulating wild-type virus (as elimination is approached) can fall below the protective threshold. Breakthrough infections are usually milder and shorter (“modified measles”) but the patient can still transmit.

SA schedule — public and private sectors

Public sector — EPI

Since 2023/2024 the EPI uses the MR (measles-rubella) vaccine from Cipla. Two routine doses:

• Dose 1: 6 months — SA is one of only two countries (the other is China, at 8 months) giving the first dose this early, to protect infants once maternal antibodies wane. The MR-Cipla PIL states a minimum age of 9 months, so the 6-month dose is off-label per the regulatory PIL, administered under NDoH/EPI policy aligned with WHO recommendations for high-transmission settings.
• Dose 2: 12 months (minimum 4-week inter-dose interval per WHO).

Private sector

MMR or MMRV (with varicella) is used, typically at 12 months and 4–6 years. Catch-up applies to older children and adults without documented immunity.

Supplementary doses (both sectors)

Additional doses are given for outbreak response (SIAs) and post-exposure prophylaxis within 72 hours. A PEP dose given before the routine first dose does not replace it — the routine schedule must still be completed.

A complete answer states the disease burden, explains how the vaccine works and its proven efficacy and safety, describes the local programme, and directly addresses common concerns.

The disease burden

Cervical cancer is a leading cause of cancer death among South African women, and the burden is amplified by HIV, which accelerates HPV-driven disease. HPV types 16 and 18 cause about 70% of cervical cancer, and almost all cervical cancer is caused by persistent high-risk HPV infection.

How the vaccine works and its efficacy

The vaccine is a non-infectious virus-like particle that raises type-specific neutralising antibody, preventing the persistent infection that leads to precancer and cancer. Vaccinated populations show large falls in high-risk HPV infection, genital warts and high-grade precancer, and early evidence of falling cervical cancer.

Safety

The HPV vaccine has an extensive safety record across tens of millions of doses. It does not cause infertility, does not affect future sexual behaviour, and the common complaints are transient injection-site reactions. Safety is continuously monitored and reported.

The South African programme

The public programme vaccinates girls through schools, at an age that protects them before exposure. Vaccinating before sexual debut gives the greatest benefit.

Addressing hesitancy

Vaccination is a means of preventing a cancer, not a statement about a child’s future behaviour; high uptake also protects the wider community, and transparent safety surveillance is what allows rare problems to be detected and acted on.

A complete answer states why a CMV vaccine is wanted, why it is difficult, the platforms under trial, and the target populations.

Why a vaccine is needed. CMV is the commonest infectious cause of congenital disability (sensorineural hearing loss and neurodevelopmental impairment) and a major pathogen in transplant recipients. No vaccine is yet licensed.

Why it is difficult. CMV establishes lifelong latency, encodes extensive immune-evasion machinery, and natural immunity does not fully prevent reinfection or congenital transmission, so the correlate of protection is uncertain.

Antigenic targets. Two are central: glycoprotein B, needed for entry into all cell types, and the pentameric complex (gH/gL/UL128-131), which mediates entry into epithelial and endothelial cells and is the target of the most potent neutralising antibodies. T cell targets such as pp65 are also pursued.

Platforms under trial. An earlier gB-subunit vaccine with MF59 gave partial efficacy (~50%) and established proof of concept. Current candidates include mRNA vaccines encoding glycoprotein B and the pentameric complex, viral-vectored constructs, and live attenuated or replication-defective whole-virus approaches.

Target populations. Adolescent girls and women of childbearing age, to prevent congenital infection, and transplant candidates, where a vaccine could reduce post-transplant disease.

Specific (hyperimmune) immunoglobulin is prepared from high-titre donors to give concentrated antibody against one agent (hepatitis B, varicella-zoster, rabies), used for targeted post-exposure protection. Normal human immunoglobulin gives broad antibody for measles or hepatitis A prophylaxis and for replacement therapy.

The other options do not determine the choice of a hyperimmune product.

Hepatitis B immunoglobulin is given with the vaccine as soon as possible after birth (within 12 hours), the combination preventing the great majority of perinatal infections.

It supplements rather than replaces the vaccine, and waiting for symptoms or proven infection would be far too late.

Circulating vaccine-derived poliovirus (cVDPV) arises when the live oral vaccine strain reverts toward virulence and spreads in under-immunised communities. It drives the move to newer oral vaccine strains and to inactivated vaccine.

The other terms describe naturally circulating virus or unrelated immunological phenomena.

Passively transferred antibody neutralises live vaccine virus, so live vaccines such as MMR or varicella are deferred for several months after an immunoglobulin product (and immunoglobulin is withheld for about two weeks after a live vaccine).

They are not given together, abandoned, or dose-adjusted.

Measles has a very high basic reproduction number (R0) of roughly 12 to 18, so the herd-immunity threshold, approximately 1 minus 1/R0, is about 95%. This is why measles is the first disease to return when coverage slips.

Lower figures suffice for less transmissible viruses but leave measles able to spread.

A monoclonal antibody is a single defined specificity, made recombinantly to a standardised potency and scalable supply. A polyclonal product is the donor-pooled, multi-epitope alternative.

Monoclonals can be made at scale, and a changing virus can escape their single epitope.

Donor screening combined with deliberate pathogen removal and inactivation (solvent-detergent treatment, low-pH incubation and nanofiltration) makes modern immunoglobulin products very safe.

Dose size, freezing, single-donor sourcing and irradiation are not how this safety is achieved; pooling many donors is in fact standard.

Types 16 and 18 cause about 70% of cervical cancer, the rationale for the original bivalent and quadrivalent vaccines. The nine-valent vaccine adds five more high-risk types, covering those responsible for roughly 90%.

The other figures misstate the type-specific attributable fraction.

Pseudouridine substitution stops innate sensors from recognising and destroying the RNA, which lowers reactogenicity and greatly increases how much antigen the cell translates. This advance, from Kariko and Weissman, made the platform practical.

mRNA acts in the cytoplasm and never enters the nucleus; pre-fusion stabilisation is a property of the encoded protein; the lipid nanoparticle provides the adjuvant effect; and self-amplification requires an encoded replicase.

South Africa gives the hepatitis B birth dose only to infants of HBsAg-positive mothers (a targeted policy), with routine hepatitis B otherwise delivered inside the hexavalent vaccine from 6 weeks. A universal birth dose, which the World Health Organization recommends, is not yet policy and is a recognised gap.

The other options misstate the current schedule.

Being injected, the inactivated vaccine raises serum antibody but little mucosal immunoglobulin A, so it does not stop the virus replicating in and shedding from the gut. It protects the individual from paralysis without fully interrupting transmission, the reason oral vaccine is still used for outbreak control.

It does induce serum antibody, individual protection and memory, and it does prevent invasion of the nervous system.

Passive antibody works best before exposure, or early after it and before symptoms, and does little once disease is established, because the virus has by then spread beyond circulating antibody. Lassa immune plasma, life-saving within the first few days but not later, is the clear example.

The other timings give little or no benefit.

The immunoglobulin provides instant passive protection in the first days, bridging the gap until the vaccine generates the patient’s own lasting antibody. It is infiltrated into the wound and gives no added benefit once the vaccine response has begun.

It does not prolong the vaccine, lower cost, or replace wound care.

Rituximab is an anti-CD20 antibody that depletes the proliferating B cells of PTLD, acting on the host cells rather than on the virus. It is a host-directed therapeutic monoclonal, not a passive antiviral antibody.

It does not neutralise EBV, replace antibody, or boost antiviral immunity.

Immune pressure can select hepatitis B surface-antigen (HBsAg) escape mutants whose altered surface antigen is less well recognised by vaccine-induced and therapeutic antibody.

The effect is limited where the surface antigen is structurally constrained; the other options do not occur.

IgG has a half-life of about three weeks, so a polyclonal immunoglobulin protects for weeks to a few months; Fc-engineered monoclonals extend this to around three months.

The other intervals misstate how long IgG persists.

Theiler attenuated the virulent Asibi strain by serial passage in chick embryo tissue to produce 17D, a live vaccine still in use and used as a backbone to carry other flavivirus antigens.

The remaining options describe inactivated, recombinant subunit, mRNA and virus-like particle approaches.

The oral rotavirus course must be completed early, with no dose given after 24 weeks of age, because the small risk of intussusception rises with age at first dose. South Africa uses a two-dose schedule at 6 and 14 weeks.

The other options are not contraindications to the vaccine.

The public programme gives HPV vaccine to girls only, as a single dose, delivered through schools.

Boys are not covered in the public sector, and the private sector offers multi-dose schedules to both sexes.

Cocooning is vaccinating those around a vulnerable person who cannot be effectively vaccinated, so the virus cannot reach them.

Ring vaccination targets the contacts around a case during an outbreak; herd immunity is the population-level version of the same idea.

A virus-like particle is made of viral capsid proteins that self-assemble into a particle resembling the virus but containing no nucleic acid, so it cannot replicate or infect while still displaying native, folded epitopes. The hepatitis B and HPV vaccines are the examples.

The other options describe inactivated, viral-vector, peptide and live attenuated vaccines respectively.

Growing the virus in eggs can select haemagglutinin mutations that subtly change the antigen, so the vaccine matches the circulating strain less well and protects less effectively. Cell-based and recombinant production avoid this.

Egg adaptation does not make the vaccine live or transmissible, does not raise neuraminidase content, and is separate from the egg-protein allergy issue.

Antibody from past exposure to common adenoviruses can neutralise the vector before it delivers its gene, reducing the response. Rare or animal-derived serotypes are chosen to avoid this.

Adenovirus vectors induce strong CD8 T cells, do not integrate, and are not contraindicated in all adults; their storage is less demanding than mRNA.

Phase III trials, in thousands to tens of thousands of participants, test protective efficacy and detect less common adverse events. Phase I addresses first-in-human safety and dose, phase II the immune response and schedule, and phase IV post-licensure surveillance.

Manufacturing scale-up is not the trial’s purpose.

NAGI is South Africa’s national immunisation technical advisory group, providing the evidence-based advice that shapes the EPI schedule and policy.

Adverse events are handled by SAHPRA and the National Immunisation Safety Committee, and polio certification sits with separate committees.

AS01B, a liposomal combination of monophosphoryl lipid A and the saponin QS-21, drives the strong CD4 T cell response behind the recombinant zoster vaccine’s durable protection.

Alum alone is a weaker adjuvant; MF59 is used in influenza vaccines; CpG 1018 is in a hepatitis B vaccine; and AS04 is used in an HPV vaccine.

Platforms that make antigen inside the host cell (live, viral-vectored and nucleic acid vaccines) load it onto major histocompatibility complex class I and prime CD8 cytotoxic T cells. Killed and subunit vaccines are taken up from outside the cell and mainly drive antibody and CD4 responses.

Inactivated and subunit vaccines induce weak CD8 responses; toxoid and polysaccharide vaccines are not viral platforms and are shown only as contrasts.

A haemagglutination-inhibition (HAI) titre of about 1:40 is accepted as a surrogate endpoint, so an influenza vaccine can be licensed on the antibody titre rather than a full disease trial.

Secretory IgA matters for mucosal protection but is not the licensing standard; CD8 responses have no licensed correlate; and neuraminidase and complement-fixation titres are not the accepted surrogate.

IgG is the only immunoglobulin actively transported across the placenta, mainly in the third trimester, so the newborn begins life with antibody mirroring the mother’s. It wanes over the first six months.

Secretory IgA is supplied by breast milk; IgM, IgE and IgD do not cross the placenta.

The varicella vaccine is a live-attenuated Oka-strain preparation, so it is contraindicated in pregnancy and in significant immunosuppression, and pregnancy should be avoided for a month after vaccination.

None of the other options is a contraindication:

• a past history of mild chickenpox
• contact with an elderly relative
• recent receipt of an inactivated vaccine
• a family history of postherpetic neuralgia

Smallpox is the only eradicated human disease, declared in 1980. The animal morbillivirus rinderpest followed in 2011. Polio and measles are current eradication targets but are not yet eradicated.

The others remain in circulation.

The Global Influenza Surveillance and Response System (GISRS) monitors circulating influenza worldwide and recommends each season’s vaccine strains, twice a year, once per hemisphere.

The other bodies handle polio, vaccine safety, routine immunisation delivery and acute flaccid paralysis surveillance respectively.

The yellow fever 17D vaccine is a live attenuated whole virus, derived by passaging the virulent Asibi strain in chick embryo tissue. It replicates in the recipient and gives durable immunity from a single dose.

The inactivated polio, recombinant hepatitis B, HPV virus-like particle and recombinant zoster vaccines are all non-living.

People with selective IgA deficiency can form anti-IgA antibodies and react anaphylactically to immunoglobulin products, so this history must be sought.

The other groups are not at specific risk on these grounds.

An mRNA vaccine is designed from the viral sequence alone and a new construct can be made in weeks, which is why the first COVID-19 mRNA vaccine was authorised in under eleven months and why mRNA influenza vaccines are being developed.

Egg-based, live attenuated, plasma-derived and virus-like particle vaccines all need the virus or protein to be grown, which is far slower.

Eradication is permanent worldwide reduction to zero, after which vaccination can stop; elimination is zero cases in a defined area, sustained by continued vaccination because the virus persists elsewhere.

The other options reverse or conflate the two.

Inactivated influenza vaccine is recommended in every pregnancy, protecting the mother and, through transferred antibody, the newborn.

The live vaccines (intranasal influenza, MMR, varicella and yellow fever) are all contraindicated in pregnancy.

Inactivated whole-virus vaccines present killed antigen that never reaches the cytoplasm, so it is loaded onto MHC class II but poorly onto MHC class I. The intact surface epitopes make excellent neutralising antibody, but CD8+ cytotoxic T cell priming is weak, which is why these vaccines are usually adjuvanted (alum, MF59, AS04) and given as several doses. Inactivated polio, hepatitis A, rabies, and inactivated influenza are examples.

The other platforms generate endogenous antigen inside host cells and so prime both antibody and CD8+ responses: live-attenuated (MMR, oral polio), viral-vector (adenovirus-vectored COVID-19, rVSV Ebola), and mRNA (BNT162b2, mRNA-1273). DNA vaccines work on the same endogenous-antigen principle but need efficient delivery and have no widely licensed human product.

Platform choice follows the protective mechanism the target virus needs: antibody-dominant threats (rabies, hepatitis B, HPV) suit subunit or inactivated vaccines, while viruses that need CD8+ control favour live-attenuated, viral-vector, or mRNA platforms. Live-attenuated vaccines are contraindicated in profound immunocompromise.

By preventing the chronic infection that drives hepatocellular carcinoma, the hepatitis B vaccine was the first to prevent a human cancer. The HPV vaccine later did the same for cervical cancer but came afterwards.

Measles and hepatitis A vaccines do not prevent cancers, and no Epstein-Barr virus vaccine is licensed.

A live vaccine still replicates, and a host without competent T cells may be unable to control even the weakened strain, allowing disseminated vaccine-strain disease. The same risk applies to the fetus in pregnancy.

Live vaccines contain no lymphotoxic adjuvant; antibody interference and the cold chain are real issues but not the reason for the contraindication; and live vaccines induce strong T cell responses.

The early 6-month dose is a deliberate measles-control measure in a setting of intense transmission and high HIV prevalence, protecting infants sooner. It is off-label against the 9-month licensed minimum and does not replace the later dose.

The other options are not the rationale.

Passively acquired maternal IgG neutralises the live measles vaccine in early infancy, causing primary vaccine failure, so the first dose is delayed until maternal antibody has waned. South Africa gives it at 6 months as a measles-control compromise.

The vaccine is live rather than inactivated, and the other options are not the reason.

• Core principle. A vaccine exposes the immune system to a non-pathogenic facsimile of a virus, priming the same memory pools as natural infection without causing disease, so re-exposure draws a fast memory response rather than a slow naïve one.
• Memory generated. Memory B cells, long-lived bone-marrow plasma cells, and memory CD4+ and CD8+ T cells (central, effector, and tissue-resident).
• Levels of protection. Sterilising immunity prevents infection (rare; HPV vaccines come close); disease prevention allows infection but blocks illness; severity reduction blocks only severe outcomes (as with drifting influenza and SARS-CoV-2).
• Mucosal versus systemic. Parenteral vaccines give serum IgG but little mucosal cover; live mucosal vaccines (oral polio, intranasal influenza) induce secretory IgA at the portal of entry and block transmission better.
• Herd immunity. Above a coverage threshold the effective reproductive number falls below one and transmission collapses; the threshold tracks R₀ (around 95% for measles), and it underpins eradication strategy. Only smallpox has been eradicated by vaccine.

• Oral poliovirus (bivalent OPV) at birth, and inactivated poliovirus (IPV) within the hexavalent vaccine.
• Hepatitis B: within the hexavalent vaccine from 6 weeks, plus a birth dose for infants of HBsAg-positive mothers.
• Rotavirus: at 6 and 14 weeks.
• Measles-rubella (MR): at 6 and 12 months.
• HPV: girls, single dose, from around 9 years.

(The hexavalent vaccine carries the polio and hepatitis B components alongside the bacterial diphtheria, tetanus, pertussis and Hib antigens.)

• Donor selection and screening of the source plasma for blood-borne viruses.
• Pathogen removal and inactivation during fractionation: solvent-detergent treatment, pasteurisation, low-pH incubation and nanofiltration.
• Together these give modern products an excellent safety record; historical transmission of hepatitis by early antibody preparations is what drove the safeguards.

Active immunity is generated by the host’s own immune system in response to antigen; passive immunity is conferred by transferring pre-formed antibody from another source.

• Natural active. Wild-type infection leaves lasting memory, protecting for decades against viruses without antigenic variation.
• Natural passive. Chiefly transplacental maternal IgG, protecting the newborn for around six to twelve months (and the reason live measles vaccine is deferred to 9 to 12 months), plus secretory IgA in colostrum.
• Combined active-plus-passive prophylaxis covers the gap when the inoculum has already arrived: rabies (immunoglobulin around the wound plus vaccine series), and the newborn of an HBsAg-positive mother (HBIG within 12 hours plus hepatitis B vaccine). Passive immunity buys time; active immunity provides durable protection.

• Indication: primary antibody deficiencies (for example X-linked agammaglobulinaemia and common variable immunodeficiency), and some secondary antibody deficiencies, where the patient cannot make protective antibody.
• How: regular intravenous or subcutaneous immunoglobulin every few weeks, supplying a broad antibody repertoire.
• Aim: maintain a protective trough level and prevent recurrent infection; this is lifelong therapy.

Withheld live vaccines: BCG, oral poliovirus vaccine, rotavirus vaccine and the measles-containing vaccine.

Why: in symptomatic HIV or AIDS the impaired cellular immunity cannot reliably control even an attenuated vaccine strain, risking disseminated vaccine-strain infection.

Children with asymptomatic HIV receive all EPI vaccines, and an additional early measles dose is given to HIV-infected infants because of their higher risk of severe measles.

Measles meets the Dahlem Conference (1997) preconditions for eradication of an infectious disease — and yet remains the only major vaccine-preventable disease that has eluded elimination over decades of effort.

Why eradication is biologically feasible

• No animal reservoir — humans are the sole natural host. There is no zoonotic source to repopulate the virus once human transmission is interrupted (cf. yellow fever).
• Single serotype — MeV is monotypic, with no antigenic drift. Vaccines made in the 1960s still neutralise contemporary wild-type strains.
• Lifelong immunity — both natural infection and complete vaccination confer durable protection.
• Highly immunogenic vaccine — a single dose seroconverts ~85% of infants at 9 months and ~95% if given later; two doses approach 100% protection.
• Clinically recognisable disease — surveillance can detect cases.
• Sensitive and specific laboratory tools — IgM serology, RT-PCR and genotyping enable confirmation and source attribution (WHO Measles Nucleotide Surveillance, MeaNS).

Why eradication is operationally hard

• R₀ of 12–18 — measles is one of the most contagious infections known. The herd-immunity threshold is ≥95% two-dose coverage, which most countries struggle to attain or sustain.
• Vaccine hesitancy — the most rapidly-growing barrier; the NEJM 2025 review highlights it as the dominant current threat.
• COVID-19 disruption — global immunisation services were set back, with measles vaccination coverage falling sharply in 2020–2022 and outbreaks resurging from 2023 onward.
• Funding and political headwinds — recent reductions in WHO and Gavi funding (the NEJM 2025 specifically notes the US withdrawal from global public-health programs) are projected to worsen LMIC coverage and global control.
• The young-infant immunity gap — infants <6 months are still protected by maternal antibody but become susceptible before reliable vaccine response is achievable, leaving a window of risk that current vaccines cannot close. New vaccine technologies (e.g. microneedle patches, formulations effective from earlier ages) are research priorities.
• Conflict and humanitarian crises — disrupt routine immunisation and the cold chain, and concentrate susceptible populations.

Where the programme is

WHO regions have set elimination targets in sequence. The Americas achieved measles elimination in 2016 (later re-established transmission); the European, Western Pacific and African Regions are working toward elimination. Globally >395,000 laboratory- confirmed measles cases were reported in 2024 (NEJM 2025), with the true number probably several-fold higher.

Eradication remains technically achievable; the obstacles are operational, political and social rather than biological.

There is no association. The MMR–autism question is one of the most thoroughly investigated in modern epidemiology, and the evidence is unequivocal: MMR vaccination does not cause autism.

Origin of the claim

The supposed link came from a 1998 case series of 12 children by Andrew Wakefield in The Lancet, proposing a link between MMR, inflammatory bowel disease and autism. The paper was:

• Methodologically poor — small, selected, uncontrolled.
• Fraudulent — Wakefield manipulated data and concealed financial conflicts of interest (he was being paid by lawyers preparing to sue vaccine manufacturers).
• Retracted by The Lancet in 2010; Wakefield was struck off the UK medical register the same year.

The evidence

Multiple large cohort and case–control studies have excluded any link:

• Madsen et al., N Engl J Med 2002 — Danish cohort of >500,000 children; no association.
• Hviid et al., Ann Intern Med 2019 — Danish cohort of >650,000 children, including high-risk subgroups (autism in family, multiple vaccinations); no association even on subgroup analysis.
• Consistent null results from multiple other countries and study designs. See DeStefano & Shimabukuro, Annu Rev Virol 2019 for the canonical review.

No biologically plausible mechanism has been identified. The temporal coincidence of MMR (given at 12–15 months in most schedules) and the typical age of autism diagnosis is what generated the original suspicion; large studies controlling for age have shown autism rates are no higher in vaccinated than in unvaccinated children.

Public-health consequences

Despite conclusive disproof, the Wakefield paper has fuelled persistent vaccine hesitancy. Declines in MMR coverage have driven measles resurgence — most prominently in the UK in the 2000s, in US outbreaks (notably 2019 and 2024–25), and in the 2019 Samoa outbreak which killed ~80 children, mostly under five. The NEJM 2025 review identifies vaccine hesitancy as the dominant current barrier to measles eradication.

Clinical implication

Counsel parents firmly and clearly: MMR does not cause autism. The original claim was fraudulent and has been comprehensively disproven. The greater risk by far is not vaccinating — measles itself causes encephalitis, pneumonia, prolonged immunosuppression, and, in 7–11 per 100,000 cases, the invariably fatal SSPE.

A complete answer gives the biological obstacles and then the main candidate approaches.

Why it is difficult

• Natural immunity is only partial: reinfection and reactivation occur in the immune, so the protective correlate is uncertain and a vaccine must outperform natural infection.
• The virus establishes lifelong latency beyond the reach of the immune response.
• Primary infection is usually silent, making it hard to target.
• There is no good animal model of the human virus.

Candidate strategies

The leading approaches target glycoprotein B and the pentameric complex, the determinants of entry and of neutralising antibody, and include messenger RNA (mRNA) platforms. The clearest signal so far is a glycoprotein B subunit vaccine that halved primary infection in seronegative women and transplant candidates. The aim is to prevent maternal primary infection and congenital disease.