L8 Infection and Immunity Vaccination and cancer

Overview

This lecture covers how immunological memory (B cell and T cell) underlies vaccine protection, what vaccines do and the types available, practical aspects of vaccination (routes, boosters, the NZ schedule), and then applies this to a specific cancer-preventing vaccine: the HPV vaccine, covering HPV biology, its route to cancer, Gardasil composition and real-world efficacy data.

Immunological memory

• As an adaptive immune response progresses, responding cells increase in quantity (more antigen-specific cells) and quality (higher-affinity antibody, or functionally polarised T cells).
• Surviving memory cells make a secondary encounter with a pathogen faster and more effective than the primary encounter.
• Historical evidence: on the Faroe Islands, measles disappeared after a 1781 epidemic and reappeared in 1846; of 7782 inhabitants 6000 caught measles (78 died), but none of the elderly survivors of the 1781 epidemic caught it again, demonstrating lifelong immunological memory.

B cell memory

• A naive B cell that encounters antigen can take two paths: directly (a slower path) to a long-lived plasma cell that secretes antibody, or via a memory B cell (B_M) intermediate, which then differentiates into a plasma cell. The memory B cell intermediate is what enables a faster response on re-exposure.
• Memory B cells arise from activated B cells and carry inherited genetic changes: they express high-affinity antibody (via somatic hypermutation) and have undergone antibody class switching (IgM to IgG, IgA or IgE).
• On re-encountering antigen, memory B cells quickly generate antibody-producing plasma cells, and can survive for years.
• Long-lived plasma cells reside in the bone marrow and are the source of antibody for months after infection.
• Primary vs secondary antibody response (serum antibody concentration vs time): in the primary response there is a latent period, then IgM rises and peaks first (~10 days), followed by IgG, which peaks later (~15 days) at a higher plateau, then declines. In the secondary response, the response is much faster and dominated by IgG (peaking ~5-10 days) reaching a much higher total antibody level than IgM, because memory cells rapidly expand and differentiate into plasma cells.

T cell memory

• Memory T cells are long-lived cells that survive after the contraction (decline) of the effector phase of an immune response. Response rises after antigen activation through an effector T cell phase, peaks, then declines during antigen clearance into a lower, sustained memory T cell phase.
• To be effective, memory T cells need to:
  • Know where to go and get there quickly: express tissue-specific homing receptors.
  • Have good “fighting equipment”: an imprinted effector phenotype from epigenetic programming, and a lower activation threshold than naive T cells.
  • Exist in sufficient numbers: high precursor frequency.
• Most current vaccines rely on B cell memory (antibody) rather than T cell memory.

Antibody effector functions

Five ways antibody acts against pathogens:

• Precipitation: makes soluble antigens insoluble, aiding elimination.
• Agglutination: links cell-bound antigens together, causing clumping.
• Neutralisation: masks dangerous parts of the pathogen (e.g. exotoxins).
• Inflammation: triggers histamine release, increasing immune cell mobility.
• Complement: complement proteins perforate the cell membrane, causing cell lysis.
  Precipitation, agglutination, neutralisation and inflammation all enhance opsonisation and phagocytosis; complement causes cell lysis directly.

What vaccines do and what they are

• Vaccines induce immunological memory without causing disease, so that on exposure to the real infectious agent the vaccinated individual shows no evidence of disease or a milder version of it.
• Vaccination also creates herd immunity: as immunisation coverage in a population rises from none, to some, to most, spread of a contagious disease becomes increasingly contained.
• Herd immunity matters because some people cannot be vaccinated or are especially vulnerable (e.g. newborns, the elderly, the immunocompromised, hospitalised patients) and rely on the immunity of others around them to reduce their exposure risk. [flag: slide only implies these vulnerable groups via photographs; it does not label each group explicitly]

Types of vaccine

• Live, weakened (attenuated) organisms.
• Inactivated virus or killed bacteria.
• Subunit vaccines: recombinant protein antigen, capsular polysaccharides, or inactivated toxins (toxoids).
• Recombinant vector vaccines, and RNA or DNA vaccines.

Features of an effective vaccine

• Safe: must not itself cause illness or death.
• Protective: must protect against illness from exposure to the live pathogen.
• Gives sustained protection: protection must last several years.
• Induces neutralising antibody: essential for pathogens (e.g. poliovirus) that infect cells that cannot be replaced, such as neurons.
• Induces protective T cells: needed for pathogens, particularly intracellular ones, that are more effectively dealt with by cell-mediated responses.
• Practical considerations: low cost per dose, biological stability, ease of administration, few side effects.

Routes of vaccination

In NZ, vaccines are given orally or by intradermal or intramuscular injection. Other routes and their trade-offs:

• Intranasal: gives mucosal and lung immunity, but has safety issues in humans.
• Aerosolised: gives mucosal and lung immunity and allows mass vaccination (nebuliser/inhaler, or spraying animals), but has safety issues in humans.
• Oral: cheap for mass vaccination and gives mucosal immunity, but limited by stability in the GI tract.
• Intramuscular: clinically relevant, gives systemic immunity, but requires a needle.
• Intradermal: clinically relevant, gives systemic immunity, requires a needle (needle-free “vaccine patch” technologies are in development).
• Intraperitoneal and intravenous: used for some candidate cancer vaccines, but have safety issues.

Why boosters are required

• Live vaccines: a single injection produces a sustained rise and plateau in antibody level, so no booster is required.
• Inactivated or subunit vaccines: antibody level rises then falls between doses, so repeated booster injections are needed to maintain and step up antibody levels over time.

History and the NZ schedule

• Vaccines have a long history: smallpox (1798) was the first, followed over the next two centuries by rabies, typhoid, cholera, plague, diphtheria and tetanus toxoids, pertussis, BCG tuberculosis vaccine, yellow fever, influenza, typhus, injected and then oral polio, live measles/mumps/rubella, anthrax, meningococcal and pneumococcal polysaccharide vaccines, adenovirus, cell-culture rabies, plasma-derived hepatitis B, and tick-borne encephalitis (through to 1981, with development continuing beyond).
• The NZ childhood immunisation schedule (ages 0-12) covers, from 6 weeks: rotavirus, diphtheria/tetanus/whooping cough/polio/hepatitis B/Hib, and pneumococcal (each as the first of a multi-dose course); further doses of these at 3 and 5 months, plus meningococcal B starting at 3 months; at 12 months, first doses of MMR and completion of the pneumococcal and meningococcal B courses; at 15 months, a Hib booster, second MMR dose, and a single chickenpox dose; a diphtheria/tetanus/whooping cough/polio booster at 4 years; HPV vaccination (2 doses, 6 months apart) from age 9; and a tetanus/diphtheria/whooping cough booster from age 11.
• Timing of vaccine delivery matters (e.g. relative to maternal antibody levels and disease exposure risk).

HPV and cancer

• Around 5% of the world’s cancers are attributed to human papillomavirus (HPV).
• HPV is the most common viral infection of the reproductive tract. Most infections are asymptomatic and 90% resolve within 2 years, but a small proportion persist and progress to precancerous lesions and, if untreated, to cancer.
• There are more than 100 types of HPV: at least 20 are oncogenic (cancer-causing), and others cause skin or genital warts. Oncogenic HPV is mainly transmitted through sexual contact.
• Genital warts form by: (1) HPV invading skin; (2) viral DNA entering skin cells; (3) infected skin cells multiplying to form a wart; (4) virus shedding and passing to others.
• HPV causes 99% of cervical cancers, and less frequently anal, vulvar, vaginal and penile cancers. HPV types 16 and 18 together cause 70% of cervical cancers.
• Oncogenic HPV is also associated with head and neck cancer (HNC): its incidence has increased over the past 15 years, 70-90% of newly diagnosed oropharyngeal cancers in the USA are HPV-positive, and HPV+ HNC is 2.3x more common in men than women.
• Harald zur Hausen published the hypothesis that HPV causes cervical cancer in 1976, and won the Nobel Prize in Medicine in 2008 for this work.
• Type-specific contribution differs by cancer site: for oropharyngeal cancer, HPV-16 accounts for 88% of type-specific infections (HPV-18 1%, other types each ≤3%); for cervical cancer, HPV-16 accounts for 59% and HPV-18 12%, with several other oncogenic types contributing smaller shares and 7% untyped.

Mechanism: HPV to cervical cancer

• Progression of untreated lesions to invasive cancer proceeds through stages: normal cervix -> squamous intraepithelial lesion (low grade, i.e. cervical intraepithelial neoplasia grade 1, then high grade, i.e. CIN2 -> CIN3) -> invasive cancer.
• Progression is associated with integration of the HPV genome into the host chromosome. In the episomal (non-integrated) state, the viral genome carries genes L1, L2, E1, E2, E4, E5, E6 and E7; early and late genes are expressed, with E6/E7 overexpressed.
• On integration into the host genome, the E2 gene is lost. Loss of E2 leads to upregulation of the oncogenes E6 and E7.
• E6 and E7 disrupt key tumour suppressor pathways, driving the progression to invasive cancer.

The HPV vaccine: Gardasil

• The first HPV vaccine was GARDASIL, a quadrivalent vaccine.
• It consists of purified virus-like particles (VLPs) made of the recombinant major capsid (L1) protein of HPV types 6 and 11 (wart-causing) and 16 and 18 (oncogenic). The L1 proteins are produced in recombinant yeast and self-assemble into VLPs, which contain the capsid protein but no nucleic acid.
• The current vaccine, GARDASIL-9, additionally covers oncogenic types 31, 33, 45, 52 and 58.
• The vaccine includes an adjuvant: amorphous aluminium hydroxyphosphate sulfate (AAHS).
• Aluminium adjuvants were once called the immunologists’ “dirty little secret” and were originally thought to act solely as antigen depots; they are now known to also stimulate the innate immune response via pattern recognition receptors (PRRs).
• Prof Ian Frazer co-developed the HPV vaccine.

HPV vaccination programme and coverage

• Most HPV infections occur within 5 years of the onset of sexual activity, so vaccination prior to onset of sexual activity is essential for prevention.
• In NZ, HPV vaccination is free for males and females aged 9-26 and offered at school.
• Immunisation coverage of eligible females (2008-2014) was low, at 50-60%.
• Cervical cancer screening is still required even after vaccination, because no vaccine is 100% effective and the quadrivalent Gardasil vaccine does not protect against oncogenic HPV types other than 16/18. Screening is via a vaginal swab to detect HPV (which can be self-administered) or via cervical cell sampling (a smear test).
• The quadrivalent vaccine was introduced in NZ in 2008. From 1 January 2017, funded access widened to people up to age 26. A two-dose regimen is funded for those aged 14 and under; a three-dose schedule is funded for those aged 15-26 inclusive. [flag: the slide states the “4 valent (Gardasil)” vaccine has replaced the “9 valent (Gardasil 9)” vaccine, which appears reversed relative to the earlier description of Gardasil-9 as the current, broader-coverage vaccine; transcribed as written on the slide, not corrected]

Efficacy and impact

• Studies of the reduction in prevalent HPV16/18 infection in the vaccine era compared with the pre-vaccine era (or contemporaneous unvaccinated females) show reductions typically in the range of roughly 14-88% across different countries, age groups and HPV types (largest reductions of 76-88% in some Australian and US adolescent cohorts).
• Prevalence has also decreased among contemporaneous unvaccinated females compared with the pre-vaccine era, demonstrating herd immunity. In Australia and NZ, there has also been a reduction in new genital wart cases among heterosexual men.
• Phase 3 clinical trials reported vaccine efficacy of 89-98% for preventing both premalignant lesions and persistent genital infections.
• Testing vaccine efficacy for head and neck cancer is more challenging than for cervical cancer because there is no identified precursor lesion, and the time to onset is much later. For the cervix, peak infection age is in the 20s, CIN2+ around the 30s, and invasive cancer peaks around the 50s. For the oropharynx, peak infection age is in the 30s-40s, with invasive cancer showing two later peaks (around 55-60 and 65-70).

Vaccines save lives

• A New Zealand news story described a 7-year-old boy who suffered severe tetanus after his parents chose not to vaccinate him (due to concerns over adverse reactions); his siblings were subsequently vaccinated. This illustrates the real-world consequences of non-vaccination.
• The WHO estimates that measles vaccination alone saved 17.1 million lives between 2000 and 2014.
• Comparing annual US disease case numbers from the 1900s (“then”) to 2010 (“now”) shows large reductions across the board: smallpox (29,005 to 0), diphtheria (21,053 to 0), pertussis (200,752 to 21,291), tetanus (580 to 8), polio (16,316 to 0), measles (530,217 to 61), mumps (162,344 to 2,528), rubella (47,745 to 6), congenital rubella syndrome (152 to 0), and Haemophilus influenzae (est. 20,000 to 270). Despite low disease rates, most diseases have not disappeared, which is why vaccination continues.
• Effective vaccines are still required for the “Big Three”: TB, HIV and malaria.

Self-test

1. Explain why a secondary (memory-driven) antibody response is faster and larger than a primary response, referring to what happens to memory B cells on re-exposure to antigen.
2. Describe the genetic and phenotypic changes that memory B cells undergo compared with naive B cells.
3. List the three requirements for memory T cells to be effective, with what each requires.
4. Describe the five antibody effector functions and how four of them relate to opsonisation and phagocytosis.
5. Define herd immunity and explain why it matters for people who cannot be vaccinated themselves.
6. List the four main categories of vaccine type, with an example of what each contains.
7. List the features of an effective vaccine according to Janeway’s Immunobiology.
8. Explain why live vaccines do not require boosters but inactivated or subunit vaccines do.
9. A family chooses not to vaccinate their child against tetanus due to concerns about side effects, and the child later develops severe tetanus. Using the lecture’s vaccine safety data, explain what this case illustrates about the risk-benefit balance of vaccination.
10. Describe the stepwise mechanism by which oncogenic HPV genome integration leads to cervical cancer, including the roles of E2, E6 and E7.
11. State what proportion of cervical cancers are caused by HPV overall, and by HPV types 16 and 18 specifically.
12. Explain why HPV vaccination is recommended before the onset of sexual activity, and why cervical screening is still required even after vaccination.
13. Distinguish the composition of the original quadrivalent Gardasil vaccine from Gardasil-9.
14. Explain why demonstrating vaccine efficacy against HPV-related head and neck cancer is more difficult than against cervical cancer.

Answers

Reveal answers

1. On first exposure, B cells differentiate either directly into long-lived plasma cells or via a memory B cell intermediate; this generates a slow IgM-dominant response peaking around 10 days, with IgG peaking later (~15 days). On re-exposure, memory B cells already exist in higher numbers and with higher-affinity, class-switched antibody, so they rapidly expand and differentiate into plasma cells, producing a faster, larger, IgG-dominated antibody response.
2. Memory B cells arise from activated B cells and carry inherited genetic changes: they express high-affinity antibody via somatic hypermutation, and have undergone antibody class switching from IgM to IgG, IgA or IgE. They can survive for years and quickly generate plasma cells on re-encountering antigen.
3. They need to know where to go and get there quickly (tissue-specific homing receptors); have good “fighting equipment” (an imprinted effector phenotype from epigenetic programming and a lower activation threshold than naive T cells); and exist in sufficient numbers (high precursor frequency).
4. Precipitation makes soluble antigen insoluble; agglutination links cell-bound antigen causing clumping; neutralisation masks dangerous pathogen components such as exotoxins; inflammation triggers histamine release increasing immune cell mobility; complement perforates the cell membrane causing lysis. Precipitation, agglutination, neutralisation and inflammation all enhance opsonisation and phagocytosis, while complement acts separately by causing direct cell lysis.
5. Herd immunity is the reduction in disease spread that occurs as more of a population becomes immunised, because there are fewer susceptible hosts to sustain transmission. It matters because people who cannot be vaccinated or are especially vulnerable (e.g. newborns, the elderly, the immunocompromised) depend on the immunity of those around them for protection. [slide only implies specific vulnerable groups via photographs, not stated explicitly]
6. Live, weakened (attenuated) organisms; inactivated virus or killed bacteria; subunit vaccines (recombinant protein antigen, capsular polysaccharides, or inactivated toxins/toxoids); and recombinant vector or RNA/DNA vaccines.
7. Safe (does not itself cause illness or death); protective (protects against illness from live pathogen exposure); gives sustained protection (lasting several years); induces neutralising antibody (essential where infected cells, e.g. neurons, cannot be replaced); induces protective T cells (for pathogens better controlled by cell-mediated immunity); and practical considerations such as low cost, biological stability, ease of administration and few side effects.
8. Live vaccines produce a sustained rise and plateau in antibody after a single dose, so no booster is needed. Inactivated or subunit vaccines produce antibody levels that rise then fall between doses, so repeated booster doses are needed to maintain and step up protection.
9. It illustrates that avoiding vaccination due to concerns over rare adverse reactions can expose a child to a severe, potentially life-threatening vaccine-preventable disease (tetanus), whereas vaccination itself carries a comparatively low risk; alongside WHO data that measles vaccination alone saved 17.1 million lives from 2000-2014, it supports the vaccine’s protective benefit outweighing its risks.
10. As untreated lesions progress (normal cervix to low-grade to high-grade squamous intraepithelial lesion to invasive cancer), the HPV genome integrates into the host chromosome. Integration causes loss of the E2 gene. Loss of E2 leads to upregulation of the E6 and E7 oncogenes, which disrupt key tumour suppressor pathways, driving progression to invasive cancer.
11. HPV causes 99% of cervical cancers overall, and HPV types 16 and 18 specifically cause 70% of cervical cancers.
12. Most HPV infections occur within 5 years of the onset of sexual activity, so vaccinating before this exposure window is essential to prevent infection. Screening is still needed afterward because no vaccine is 100% effective, and the quadrivalent vaccine does not protect against oncogenic HPV types other than 16/18, so vaccinated individuals can still develop HPV-related precancerous change from other types.
13. The original quadrivalent Gardasil covers HPV types 6 and 11 (wart-causing) and 16 and 18 (oncogenic). Gardasil-9 additionally covers oncogenic types 31, 33, 45, 52 and 58, giving broader protection against oncogenic types.
14. Testing efficacy against head and neck cancer is harder because there is no identified precursor lesion (unlike cervical intraepithelial neoplasia for cervical cancer) to use as an intermediate endpoint, and the time from infection to invasive cancer onset is much later and more variable (peaks around 55-60 and 65-70 years, versus around the 50s for cervical cancer).