Vaccine Types and Platforms — Questions

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.

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.

• 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 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.

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.

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.

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.

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.

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.

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.

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.

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.