PHCM9782 Module 2 Week 1

Epidemiology of VPDs

Professor James Wood, School of Population Health

 Why VPDs?
• Practical grouping based on similarities in prevention approach
and implementation
• Majority of VPDs are acute viral infections that induce long-lasting
immunity – however, many important exceptions
• Currently 25 VPDs listed in Australia’s immunization handbook.
• National immunization program at ~$500 million annual
expenditure in 2021-22 (similar to e.g. intravenous
immunoglobulin program). Highly effective program but newer
vaccines are expensive.

Sources: https://immunisationhandbook.health.gov.au/contents/vaccine-preventable-diseases
https://www.anao.gov.au/work/performance-audit/improving-immunisation-coverage
Smallpox and vaccines
• Smallpox (variola) a member of the Orthopoxvirus genera and closely related to
monkeypox (now Mpox).
• Very severe infection - case-fatality rates of around 50% in young children and the
elderly, somewhat lower in-between.
• Present in humans for at least 2000 years – likely to have first arisen in last 10,000
years with large stable human populations.
• Recognition of protection against re-infection led to efforts at inoculation with
liquid from smallpox pustules
• Jenner’s publication on prevention using cowpox inoculation led to rapid
international dissemination.
• Not surprising – analysis by Daniel Bernoulli indicated that elimination of
smallpox would raise median life-expectancy by >10 years!
Sources: Florey Lecture 1983 (Frank Fenner) https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.1983.0039
https://www.medicine.mcgill.ca/epidemiology/hanley/bios601/competingRisks/DanielBernoulli.pdf
 Successful eradication program
Continent-level progress on elimination Features that favoured eradication

8. R0 in range 3-6
9. 2-3 week generation interval

Measles status Polio status

Smallpox eradication an amazing achievement – relatively slow spread of infection and moderate R0 factors now recognized as
greatly assisting elimination efforts.
Proof of principle – but extending to other serious infections like Measles and Polio has been difficult.
Source: Florey Lecture 1983 (Frank Fenner) https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.1983.0039
Why is elimination possible?
• If each infectious case generates <1 secondary infection, infection will die out in a
population (elimination)
• With vaccines that prevent infection, potential to achieve this with organized vaccination
programs
• If we have an infection where there are R0 secondary infections per case on average in a
fully susceptible population as well as
• Human-only host
• Long-term immunity (low lifetime probability of reinfection)
• Then herd immunity can be sustained through e.g. routine immunization if R0-1 out of
every R0 people is effectively immunized.
• Fairly easy for a low R0 of 2 (1/2 = 50%), a feasible challenge for a smallpox-like R0 of 5
(4/5=80%) but much harder for a disease like measles where R0~15 (14/15 or ~94%).
However…
• Formula requires human-only host and long-term immunity from vaccination
• Does not apply to e.g. COVID-19 or influenza (immune duration even from
infection of order 1-5 years due to viral evolution)
• Does not apply to e.g. Yellow Fever or Japanese Encephalitis (multiple hosts)
• May require multiple doses of vaccine to achieve long-term immunity (e.g. polio)
• Also … vaccine programs can be highly effective even without quickly achieving
elimination
• Whooping cough (can prevent almost all severe disease)
• HPV and Hepatitis B vaccines – may eventually achieve partial or complete elimination but
takes many years
• Vaccines for the elderly – in general aimed at preventing severe disease not infection.
 Broad epidemiological classes within VPDs
Primarily human-human Potential to greatly reduce Fecal-oral/water human-human
transmission with vaccines
Respiratory/skin-skin Cholera (also environmental reservoirs)
• Diphtheria Hepatitis A
• Haemophilus influenzae type b (Hib) Poliomyelitis
• Influenza (flu) Rotavirus
• Measles Typhoid fever
• Meningococcal disease
Environmental reservoir Individual protection only
• Mumps
• Pertussis (whooping cough) • Tetanus
• Pneumococcal disease Animal hosts Primarily individual protection
• Rubella • Japanese encephalitis (water birds, pigs, human
• Tuberculosis dead-end - requires certain mosquito species to be
• Varicella (chickenpox), Zoster (herpes zoster) present)
STI – Human papillomavirus (HPV) • Q fever (typically domestic animals and humans)
Bloodborne – Hepatitis B • Rabies and other lyssaviruses (e.g. dogs or bats,
human dead-end)
• Yellow fever (humans + non-human primates)
 Tetanus in Australia
• Tetanus is a very severe disease caused by the neurotoxin from Clostridium tetani bacteria,
released when wounds become infected
• Dormant spores plentiful and long-lasting in the environment with risk largely from
environmental exposure. Urbanisation typically reduces risk
• Vaccines target the toxin and prevent severe consequences of infection
• Very high uptake in Australia of tetanus-containing vaccine – disease now very rare
• International context – maternal and neonatal tetanus a focus for elimination
Australian mortality time-series Risk of hospitalization continues
to decline in Australia

Sources: https://www.aihw.gov.au/getmedia/f877a2da-23e3-4516-948f-df05ca7ceb43/aihw-phe-236_Tetanus.pdf.aspx
https://commons.wikimedia.org/wiki/File:Clostridium_Tetani.svg
https://www.who.int/initiatives/maternal-and-neonatal-tetanus-elimination-(mnte)
 Japanese encephalitis
• Caused by the Japanese Encephalitis Virus, one of several Flaviviruses that cause significant
disease in humans through mosquito/tick bites
• Natural host wild birds (e.g. herons and egrets) but pigs play “amplifying” role in transmission.
Humans dead-end hosts - small proportion develop potentially fatal encephalitis.
• Not seen as endemic in Australia but significant number of severe cases in early 2022 (big wet)
• Vaccination effective and provides long-term immunity – but no impact on transmission from
human vaccination and limited impact from pig vaccination
Modelled ecological niche for Culex annulirostris
(mosquito vector of most interest)

Sources: Holbrook et. al. https://www.mdpi.com/1999-4915/9/5/97/htm

Furlong et. al. https://www.mdpi.com/2414-6366/7/12/393
 Human papillomavirus (HPV)
• HPV very common sexually transmitted infection – mostly
asymptomatic but persistent infection primary risk for cervical
cancer as well as certain anal and oro-pharyngeal cancers.
• Causal role of HPV in cervical cancer postulated due to presence of
HPV in relevant lesions and then confirmed in detailed
epidemiological studies.
• Raised potential for a vaccine –developed using novel “virus-like-
particle” technology. Introduced in 2006 in Australia in girls only – Pre-vaccine prevalence in Australian women (15+)
universal routine program from 2013.
• Vaccine is much more effective than infection at producing
immunity –now moving to 1 dose program in Australia (trialled as
3 doses).
• Large number of HPV types… current vaccine includes 7 cancer-
causing and 2 warts-causing types. Concerns about replacement
disease have not eventuated.

Sources: cool video on VLP construction here https://www.youtube.com/watch?v=XYtV034mQvQ

Garland et. al. BMC Medicine 2011 https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-104
https://commons.wikimedia.org/wiki/File:5keq.png based on Guan e.t al. Structure 2017. https://www.sciencedirect.com/science/article/pii/S0969212616303914?via%3Dihub
 Impact of HPV vaccination in Australia
• Cervical cancer delayed outcome from HPV infection (10-30 years). Proportion of sentinel Australian STI clinic
Means significant delays to observe desired effects of vaccine program. visits for genital warts
• However, rapid effect on genital warts (types 6,11 included in Merck
vaccine) – surveillance from STI clinics can demonstrate this.
• Predicted impact of program has also led to major changes in how we
screen for cervical cancer (HPV testing, reduced age range, less frequent)
• Full elimination unlikely (non vaccine types) but ~90% reduction feasible.
Predicted mortality from cervical cancer in Australia, with (red) and
without (blue) screening

Sources: Chow et. al. Lancet ID (2021) https://www.sciencedirect.com/science/article/pii/S1473309921000712?via%3Dihub

Screening renewal: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1276-public
Hall et. al. Lancet Public Health (2019): https://www.sciencedirect.com/science/article/pii/S246826671830183X
 Measles – a potential eradication target
• Measles caused by measles morbillivirus, a genus including important animal
infections such as canine distemper virus (many mammal hosts) and rinderpest
(cattle, other even-toed ungulates), successfully eradicated in 2011.
• Moderate severity (CFR >1/1000 in infants and adults) and high infectiousness
(R0>10) make this a disease of high consequence globally, particularly infant
mortality in low-income countries.
• However, aside from high infectiousness that begins before rash develops, generally
meets other criteria for eradication:
• High severity (at a population level)
• Very few subclinical cases
• No recurrence of infection in immunocompetent hosts
• Only one serotype (vaccine, infection protect against all lineages)
• Highly effective vaccine available
• No animal/environmental reservoirs
• Generation interval 1-2 weeks (facilitates ring vaccination)
• Primary difficulty is getting routine vaccine coverage up to ~95% with 2 doses of
measles containing vaccine
 Measles in NYC (1891-1984)
Measles epidemics shaped by
demographic change cycle
• New susceptibles are born
• Older immune people die
• Population immunity
declines until new epidemic
forms and then is high again
• Iterate…

Pattern is influenced by rates of

What happened
births and deaths – if these
here?
decline, epidemics may become
every 2 years or every 3 years.

Strongly influenced by other

sources of immunity
 Progress on elimination
Country level: Australia (declared 2014) WHO region level: PAHO announced elimination in 2016

Sources: Heywood et. Al. Bull. WHO (2009) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649598/

Andrus et. Al. Vaccine, 2011 https://www.sciencedirect.com/science/article/pii/S0264410X11006049
 Reported measles incidence per million persons

Global progress
• Substantial global progress from 2000-16
• More mixed since then (Western Pacific doing better,
most other areas doing worse).
• Current concerns about resurgence due to COVID-19
interrupting routine immunisation

What does this reflect?

Sources: WPRO Measles Rubella Bulletin January 2023 https://apps.who.int/iris/handle/10665/366144

Patel et al. MMWR 2019 https://www.cdc.gov/mmwr/volumes/68/wr/mm6848a1.htm
Causey et. al. Lancet 2021 https://www.thelancet.com/article/S0140-6736(21)01337-4/fulltext
 Relevance to Australia
Google news search for measles at 1.20pm AEDT 20/02/2023
Very high 2-dose measles vaccine coverage and effective
outbreak responses (tracing, vaccination etc.)

No risk of large-scale outbreaks (e.g. 1000s of cases) but

smaller outbreaks possible (10s, 100s. E.g. Sydney outbreak
with almost 200 cases in 2012 – superspreading events
combined with lower than average immunization rates in
affected population. However, majority of imported cases
lead to 0 secondary infections.

Breakthrough cases do occur but limited infectiousness

Source: WPSRJ 2014 Najjar et. al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984967/
 Vaccines against bacterial pneumonia and
invasive disease
• Effective (protein conjugated) vaccines against Haemophilus Influenzae (1987), Neisseria
Meningitides (MenC 1999) and Streptococcus pneumonaie (PCV7 2000) were first introduced.
• These 3 groups of encapsulated bacteria are commonly carried (asymptomatically) by infants and
young children in the nasopharynx but can cause very serious invasive disease (bloodstream
infections, meningitis) as well as pneumonia and ear infections.
• These conjugate vaccines elicit a strong immune response that not only prevents invasive disease
but also protects against carriage.
US data
~2/3rds of cases had meningitis
Mortality ~4%
/100,000 in <5y

/100,000
Significant sequelae 15-30%
How is this scale of
change possible? Invasive pneumococcal disease (USA)

Why did disease drop in 65+?

 But… replacement disease
UK data
More than 90 individual serotypes for pneumococcal
disease.

Have seen sequence of reduction in carriage in vaccine

types and then replacement by non-vaccine types for 7v What happened here?
and 13v pneumococcal vaccine (and similar effect
expected for new 20v vaccine).

Overall benefit much smaller than initial effects seen in

the US – has led to revised approaches to development of
bacterial vaccines (e.g. against Group A Streptococcus).

Note seen sustained ~40% reduction in all-ages invasive

pneumococcal disease in Australia.

Sources: Choi et. al. 2011 PLoS One https://pubmed.ncbi.nlm.nih.gov/22022559/

Davies et. al. 2019 Nature Genetics https://www.nature.com/articles/s41588-019-0417-8
Vaccines in adults and the elderly
• Significant recent developments in vaccines against disease in adults and the
elderly (beyond influenza and polysaccharide pneumococcal vaccines)
• Zostavax and Shingrix for prevention of Shingles
• 13v conjugate pneumococcal vaccines for older adults (protection against pneumonia)
• Covid-19 vaccines
• Vaccines against respiratory syncytial virus (RSV)
• Rationale – large and increasing burden of infection in older people as global
population ages (decline in immune responses on average).
• Aim to prevent disease but not necessarily influence transmission.
• Cost of vaccine development a significant challenge (vaccines very expensive –
public funding can be contentious)
 Topics covered
• VPDs as a practical classification
• Smallpox and eradication criteria
• How reservoirs of infection influence gains from vaccination
• Examples – tetanus, JEV and HPV
• Measles and elimination efforts
• Vaccines against invasive bacteria and the problems of serotype replacement
• Some comments on vaccines in the elderly
Things I didn’t cover
• Technologies, immunology etc. (see guest lecture)
• Important respiratory and enteric vaccines (e.g. flu, covid, pertussis, diptheria, polio, rotavirus)
• Immunotherapeutics and vaccine-like products (e.g. nirsevimab for RSV)
• Globally important partial VPDs such as malaria, dengue, cholera etc.