journal club meta-analysis of HPV vaccination trials and their impact on prevention of carcinoma of cervix

1. Population-level impact and herd effects
following the
introduction of human papillomavirus vaccination
programmes: updated systematic review and
meta-analysis
JOURNAL CLUB – PRESENTED BY DR FARAZ BADAR
MODERATOR : DR SUSOVAN BANNERJIE
DATED : 17/07/2019

2. • BACKGROUND
• INTRODUCTION
• METHODS
• RESULTS
• DISCUSSION
• CONCLUSION
• HPV VACCINATION SCENARIO IN INDIA

3. BACKGROUND

5. HPV in Oncology : brief review
Papillomaviruses are double-stranded DNA viruses that constitute the
Papillomavirus genus of the Papillomaviridae family.
High-risk HPV genotypes : Total 15 (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,
59, 68, 73 and 82)
• HPV type 16 and 18 (cause approximately 70 percent of all cervical cancers
worldwide)
• HPV types 16 and 18 also cause nearly 90 percent of anal cancers and a
significant proportion of oropharyngeal cancer, vulvar and vaginal cancer,
and penile cancer.
• HPV types 31, 33, 45, 52, and 58 (cause an additional 20 percent)
Low risk HPV types : Total 11 (types 6, 11, 40, 42, 43, 44, 54, 61, 70, 81 and
CP6108)
• HPV types 6 and 11 cause approximately 90 percent of anogenital warts

6. Background continued …
• More than 200 types of HPV (40 are sexually transmitted)
• Can be subdivided into cutaneous or mucosal categories based upon
their tissue tropism.
• Non-enveloped, capsid viruses with an eight kilo base circular
genome that encodes eight genes including two encapsulating
structural proteins, L1 and L2.
• The L1 protein, expressed recombinantly in a cell-culture system, self-
assembles in the absence of the viral genome to form a virus-like
particle (VLP)
• The L1 VLP is the immunogen used in the HPV vaccines.

7. PATHOGENESIS
• The initiating event in cervical dysplasia and carcinogenesis
• Gains access to the basal layer of the cervical epithelium, which becomes the viral
reservoir
• The HPV genome integrates into the host cell chromosomes in cervical epithelial cells
and codes for six early and two late open reading frame proteins, of which three (E5,
E6,and E7) alter cellular proliferation.
• Two viral genes, E6 and E7, are typically expressed in HPV-positive cervical-cancer cells.
• The E6 protein inactivates the major tumor suppressor p53; this causes chromosomal
instability, inhibits apoptosis, and activates telomerase.
• E7 protein binds the hypophosphorylated (active) form of retinoblastoma protein (Rb)
and promotes its degradation via the proteasome pathway resulting in a loss of
regulation of the cell’s proliferation and immortalization

8. DEVELOPMENT OF HPV VACCINE
• Recombinant DNA technology is used to express the L1 major capsid
protein of HPV in yeasts (Saccharomyces cerevisiae), which self-
assemble to form empty shells resembling a virus, called virus-like
particles (VLPs).
• VLPs  Same outer L1 protein coat as HPV but genetic material is
absent.
• The vaccine uses these VLPs as antigens to induce a strong protective
immune response.
• If an exposure occurs, the vaccinated person's antibodies against the
L1 protein will coat the virus and prevent it from releasing its genetic
material.

10. DOSAGE AND SCHEDULE
• Vaccine dose is 0.5 mL given intramuscularly, either in the deltoid muscle or in the
anterolateral thigh.
• It is available as a sterile suspension for injection in a single-dose vial or a prefilled
syringe, which should be shaken well before use.
• The recommended age for initiation of vaccination is 9–12 years.
• Catch-up vaccination is permitted up to the age of 26 years.
• A total of three doses at 0, 2 and 6 months are recommended with Gardasil™ or 0, 1 and
6 months with Cervarix™ (minimum interval of 4 weeks between the first and the second
dose, 12 weeks between the second and third dose and 24 weeks between the first and
third dose).
• HPV vaccines can be given simultaneously with other vaccines such as Hepatitis B and
Tdap.
• At present, there is no data to support the use of boosters.
• If the HPV vaccine schedule is interrupted, the vaccine series need not to be restarted. If
the series is interrupted after the first dose, the second dose should be administered as
soon as possible.

12. INTRODUCTION

13. INTRODUCTION
• 99 countries and territories have introduced HPV vaccination
programmes so far.
• In 2015, the authors did a systematic review and meta-
analysis of the population-level impact of HPV vaccination,
including data from nine high-income countries up to 4 years
after the introduction of HPV vaccination

15. Findings
• 20 studies, from 9 high-income countries and representing more than 140 million person-years of follow-up.
• HPV type 16 and 18 infection decreased significantly by 68% (RR 0·32, 95% CI 0·19–0·52) in countries with
female vaccination coverage of at least 50%
• Anogenital warts decreased significantly by 61% (0·39, 0·22–0·71) in girls 13–19 years of age.
• HPV types 31, 33 and 45 decreased by 28% (RR 0·72, 95% CI 0·54–0·96) in 13-19 years age group of girls
which
suggests cross protection.
• Anogenital warts decreased significantly in boys younger than 20 years of age (RR 0·66 [95% CI 0·47–0·91]) and
in women 20–39 years of age (RR 0·68 [95% CI 0·51–0·89]), which suggests herd effects.
• In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18
infection (RR 0·50, 95% CI 0·34–0·74]) and in anogenital warts (0·86 [95% CI 0·79–0·94]) occurred in girls

16. LIMITATIONS AND NEED FOR UPDATE
• In the meta-analysis of 2015, the number of years after vaccination
was insufficient to examine the impact of HPV vaccination on the
occurrence of cervical intraepithelial neoplasia grade 2+ (CIN2+).
• CIN2+ may take several years to develop, and is the most proximal
outcome for cervical cancer
• Authors updated their meta analysis for 3 reasons :
1. Countries and data have increased  More power to study
2. Ability to analyze CIN2+ because of increased duration
3. WHO position has changed in 2016  from single age cohort to
multiple age cohort vaccination

17. AIMS AND OBJECTIVES
A. Update and summarize the most recent evidence about the
population-level impact of girls-only HPV vaccination on HPV
infections and anogenital wart diagnoses among girls, boys,
women, and men;
B. Summarize new evidence about the population-level impact of
girls-only HPV vaccination on CIN2+ occurrence among screened
girls and women
C. Compare the population-level impact of HPV vaccination on
anogenital wart diagnoses and CIN2+ occurrence between
countries that have implemented either a single or a multiple age-
cohort vaccination strategy.

18. METHODS

19. ELIGIBILITY CRITERIA
• The authors reported their methods in accordance with the
preferred reporting items for systematic reviews and meta-
analyses (PRISMA) guidelines
Studies were eligible if they compared the frequency
(prevalence or incidence) of at least one HPV-related endpoint
1. Genital HPV infections
2. Anogenital wart diagnoses or
3. Histologically confirmed CIN2+
between pre-vaccination and post-vaccination periods among
the general population and if they used the same population
sources and recruitment methods before and after vaccination.

20. SEARCH STRATEGY
• To update the first systematic review (of studies published between
Jan 1, 2007, and Feb 28, 2014), the authors searched MEDLINE and
Embase for studies published between Feb 1, 2014, and Oct 11, 2018,
with the same combination of MeSH terms, title, or abstract words:
(“papillomavirus vaccine”, “papillomavirus vaccination”, “HPV
vaccine”, or “HPV vaccination”) and (“program evaluation”,
“population surveillance”, “sentinel surveillance”, “incidence”, or
prevalence”), and (“papillomavirus infection”, “condylomata
acuminata”, “anogenital warts”, “cervical intraepithelial neoplasia”,
“cervical dysplasia”, “uterine cervical neoplasm”, or “HPV related
diseases”)

21. DATA ANALYSIS
• The primary assessment was the relative risk (RR) comparing the
frequency of HPV-related endpoints between the pre-vaccination and
post-vaccination periods.
• For HPV infection, authors focused on three subgroups of HPV types:
a) HPV 16 and 18,
b) HPV 31, 33, and 45, and
c) all high-risk types except HPV 16 and 18

22. STEPS
• The authors distributed the tasks amongst themselves that included :
• Extraction of the study characteristics and outcomes using a standardized
form : MD, .B, and NP
• Assessment of the methodological quality of all studies, independently
from the authors of the original studies : MD, .B, and NP
• Assessment of Potential bias and risk of confounding
• MD contacted all corresponding authors of eligible studies to request a re-
analysis of their data using the same data stratifications (eg, by age group
or HPV type) to allow comparison between studies and pooling.

23. STRATIFICATION
• For all endpoints : stratified analyses by sex, age, and years since the
introduction of HPV vaccination.
• Divided the Relative Risks into two time categories  1-4 years and 5-
8 years (5-9 years for CIN2+)
• For ano-genital warts : Stratified by the type of vaccine administered,
since only the quadrivalent vaccine includes HPV 6 and 11

24. • For anogenital warts and CIN2+, studies presented the annual
frequency (prevalence or incidence) of the endpoint over time for the
pre-vaccination and post-vaccination periods.
• For these endpoints, authors estimated the pre-vaccination frequency
by aggregating the data for up to 3 years before vaccination and
calculated the crude RR by dividing each post-vaccination year by the
pre-vaccination estimate.
• Used random-effects models on a log scale in Review Manager
(version 5.3.5).

25. HPV
• Could not do multivariate meta regression analysis due to small number of
studies for each endpoint.
• They did subgroup analyses to identify the main sources of heterogeneity
between studies.
• For HPV infections, the vaccination status was directly available for all study
participants (except for one study).
• Dichotomized the studies into either high (≥50%) or low (<50%) vaccination
coverage

26. ANOGENITAL WARTS
• Most studies were based on population or insurance registries for
anogenital warts
• Dichotomised studies into either :
1. Medium or high proportion of people vaccinated (if the country or
region vaccinated multiple cohorts of girls, with a vaccination
coverage ≥50% for at least two doses among the routine cohort)
2. Low proportion of people vaccinated (if the country or region
vaccinated single cohorts of girls or had a coverage for at least two
doses <50% among the routine cohort).

27. CIN2+
• For CIN2+, studies were based on screened girls and women from
screening registries.
• Because CIN2+ detection can be influenced by screening
recommendations and participation, so authors examined the effect
of HPV testing during the study period, and the effect of an
introduction of HPV testing, older age at screening start, and changes
in the screening interval during the study period.

28. RESULTS

29. • Authors identified 1702 potentially eligible articles, and included 65
articles (from 40 studies) in this systematic review and meta-analysis:
23 for HPV infection
29 for anogenital warts
 13 for CIN2+
• The studies were done in 14 high-income countries and cumulated
data from more than 60 million individuals over 8 years (2007–15; 9
years for CIN2+)

31. • As of 2015, 12 (86%) of the 14 countries included in this review were
vaccinating girls and women only, with three doses of the bivalent or
quadrivalent vaccine.
• Exceptions were Australia and the USA.
• Australia switched to a gender-neutral programme in 2013
• USA recommended gender-neutral vaccination in 2011.
• The age of routine vaccination varied slightly between countries, from
10 to 13 years old.
• Most countries with multi-cohort vaccination targeted girls up to 18
years of age through routine and catch-up programmes.

32. • Australia, the USA, and Denmark targeted women up to 26 years of
age (with decreasing coverage as age increased)
• All studies were of sufficiently high methodological quality to be
included in the meta-analysis.
• No studies were found with risk of serious bias.

33. END POINT 1 : HPV INFECTION IN FEMALES
AGE COHORT % DECREASE AFTER
5- 8 YEARS
RELATIVE RISK CONFIDENCE
INTERVAL
HPV 16 AND 18
PREVALENCE
13- 19 YEARS 83 0.17 0.11-0.25
20-24 YEARS 66 0.34 0.23-0.49
25-29 YEARS 37 0.63 0.41-0.97
HPV 31, 33,45
PREVALENCE
13-19 YEARS 54 0.46 0.33-0.66
20 – 24 YEARS 28 0.72 0.47-1.10

34. END POINT 1 : HPV INFECTION IN FEMALES
• In subgroup analyses, studies in which participants had a high
vaccination coverage (≥50%) generally had a greater decrease in
prevalence of HPV 16 and 18 and HPV 31, 33, and 45 compared with
studies in which participants had a low vaccination coverage (<50%).
• Studies that used clinic-based data also showed greater decreases in
prevalence of HPV 16 and 18 compared with studies that used
population-based data.

35. END POINT 1 : HPV INFECTION (FOREST PLOT)

36. END POINT 1 : HPV INFECTION IN MALES
• Two studies were available for genital HPV infections among boys and
men.
• Nonsignificant decreases in prevalence of HPV 16 and 18 (RR 0.35,
95% CI 0.09–1.40) and HPV 31, 33, and 45 (RR 0.31, 95% CI 0.06–
1.58) were observed among boys aged 16–19 years in the first 4 years
of girls-only vaccination.

37. END POINT 2 : ANOGENITAL WART
DIAGNOSIS
• In the first 4 years following implementation of quadrivalent HPV
vaccination, anogenital wart diagnoses decreased significantly among
girls and women aged 15–19, 20–24 years, and 25–29 years.
• Nonsignificant but substantial decreases were observed among
unvaccinated boys aged 15–19 years
• After 5–8 years of HPV vaccination, decreases in anogenital wart
diagnoses were significant for girls and women aged 15–29 years and
for boys and men aged 15–24 years.

38. END POINT 2 : ANOGENITAL WART
DIAGNOSIS
• In subgroup analyses, studies in countries with multi-cohort
vaccination and high vaccination coverage showed significantly
greater decreases in anogenital wart diagnoses among girls, women,
boys, and men aged 14–29 years, compared with studies in countries
with single cohort vaccination or low vaccination coverage.
• Three studies examined changes in anogenital wart diagnoses
following the implementation of bivalent vaccination and results
suggest a slight decrease among girls and women aged 15–19 and
20–24 years, and boys aged 15–19 years.

39. END POINT 2 : ANOGENITAL WART
DIAGNOSIS
AGE COHORT % DECREASE AFTER
5- 8 YEARS
RELATIVE RISK CONFIDENCE
INTERVAL
GIRLS AND WOMEN 15- 19 YEARS 67 0.33 0.24-0.46
20-24 YEARS 54 0.46 0.36-0.60
25-29 YEARS 31 0.69 0.53-0.89
BOYS AND MEN 15-19 YEARS 48 0.52 0.37-0.75
20 – 24 YEARS 32 0.68 0.47-0.98

40. END POINT 2 : ANOGENITAL WART
DIAGNOSIS (FOREST PLOT)

42. END POINT 3 : CIN 2+
AGE COHORT % DECREASE
/INCREASE AFTER 5-
9 YEARS
RELATIVE RISK CONFIDENCE
INTERVAL
GIRLS AND WOMEN 15- 19 YEARS ↓67 0.49 0.42-0.53
20-24 YEARS ↓31 0.69 0.57-0.84
25-29 YEARS ↑19 1.19 1.06-1.32
30-39 YEARS ↑23 1.23 1.13-1.34

43. • In subgroup analyses, countries with multi cohort vaccination high
routine vaccination coverage had greater decreases in CIN2+ among
girls and women aged 15–24 years than the country with single-
cohort vaccination or low routine vaccination coverage.
• Subgroup analyses also showed that increases in CIN2+ among
women aged 25–29 years in the post-vaccination period were
significantly greater in the country with single-cohort vaccination or
low routine vaccination coverage.

44. END POINT 3 : CIN 2+ (FOREST PLOT)

45. END POINT 3 : CIN 2+

46. DISCUSSION

47. • The meta analysis shows significant and substantial impact of HPV
vaccination on three HPV-related endpoints in the first 9 years after
the start of HPV vaccination.
• HPV 16 and 18 infections, anogenital wart diagnoses, and CIN2+
decreased significantly among girls and women.
• Evidence of vaccine cross-protection (HPV 31, 33, and 45 decreased
significantly among girls younger than 20 years)
• Evidence of herd effects from girls-only vaccination programmes
(anogenital warts diagnoses decreased significantly among boys and
men).

48. MULTI COHORT vs SINGLE COHORT & HIGH vs
LOW ROUTINE COVERAGE
• This meta-analysis illustrates the greater and faster direct impact and
herd effects of HPV vaccination in countries with both multi-cohort
vaccination and high routine vaccination coverage, compared with
countries with single-cohort vaccination or low routine vaccination
coverage.
• For example, after 5–8 years of HPV vaccination, anogenital wart
diagnoses declined by 88% among girls and 86% among boys younger
than 20 years in countries with multi-cohort vaccination and high
routine vaccination coverage, compared with 44% among girls and 1%
among boys in countries with single-cohort vaccination and low
routine vaccination coverage.

49. • After 5–8 years of girls-only vaccination in countries with multi-cohort
vaccination and high routine vaccination coverage, reductions in
anogenital wart diagnoses were 44 percentage points greater among
girls aged 15–19 years than among girls the same age in countries
with single-cohort vaccination or low routine vaccination coverage.
• Reductions in CIN2+ were more than 100 percentage points greater.
• Reductions in anogenital wart diagnoses among boys aged 15–19
years were 85 percentage points (86% vs 1%)
• The greater impact of multi-cohort vaccination was similar when
restricting the analyses to countries with high routine vaccination
coverage.

50. REINFORCING WHO POSITION
• Results reinforce WHO’s recently revised position on HPV vaccination.
• To obtain faster and greater population-level impact, WHO revised its
position in 2016 and recommended HPV vaccination of multiple age
cohorts of girls (9–14 years old) when the vaccine is introduced in a
country, rather than vaccination of a single cohort.
• Optimal number of age cohorts to vaccinate  open

51. CIN 2+
• Study presents First pooled estimates of the population-level impact
of HPV vaccination on CIN2+.
• The results provide strong evidence of HPV vaccination working to
prevent cervical cancer in real world settings, as both the cause (high-
risk HPV infection) and proximal disease endpoint (CIN2+) are
significantly declining.

52. POTENTIAL OF IMPACTING CERVICAL
SCREENING PROGRAMMES
• The results can also inform potential changes to cervical screening
programmes.
• Substantial declines in high-risk HPV types and CIN2+ might allow for
screening to start at an older age and for longer screening intervals.
• The decreasing HPV prevalence also support a switch from cytology
alone to primary HPV testing followed by cytology triage to benefit
from the higher sensitivity of HPV testing to detect pre-cancerous
lesions and higher specificity of cytology, without substantially
increasing the number of false positive results.

53. EXPLAINING THE INCREASE IN ENDPOINTS IN
CERTAIN SUBGROUPS
Results suggesting increases in HPV-related endpoints among
population subgroups not targeted by vaccination:
a. high-risk non-vaccine HPV types
b. anogenital wart diagnoses among men aged 25–39 years,
c. CIN2+ among screened women aged 25–39 years
EXPLANATION POINT 1 : increases in the three HPV-related
endpoints could reflect increases in sexual activity.
• Over the past 10–20 years, the number of sexual partners per
individual has increased, and the age at initiation of sexual activity
has decreased in several high-income countries.

54. • EXPLANATION POINT 2 : Increases in high-risk non-vaccine HPV types
could partly be explained by
1. HPV 16 and 18 unmasking  apparent increased detection of non-
vaccine HPV types in a post-vaccination population with fewer HPV
16 and 18 infections, which could have masked detection of other
HPV types before vaccination.
2. Type replacement  increased prevalence of non-vaccine HPV
types occupying the ecological niche created by prevention of HPV
16 and 18 infections

55. • EXPLANATION POINT 3 : Increases in anogenital wart diagnoses could
be partly explained by increased knowledge, awareness, and health-
seeking behavior of the general population about anogenital warts,
and by better diagnosis and reporting by health professionals.
• EXPLANATION POINT 4 : Increases in CIN2+ could be attributable to
changes in screening recommendations, tests, and participation
documented in several countries.

56. ADDITIONAL STRENGTHS
• All corresponding authors of the studies were contacted in order to
have standardized age groups and HPV endpoints, permitting pooling
of results.
• Sufficient statistical power due to large pooled sample size and 8
years of follow up (9 years for CIN2 +)

57. LIMITATIONS
1. Causality between HPV vaccination and the observed changes in
HPV-related endpoints cannot be concluded definitively.
2. Number of studies too small to do multivariate meta-regression
analyses.
3. All studies from High-income countries. Caution while extapolating
to low income countries.
4. Significant heterogeneity acceptable or not
5. Clubbing together of multi cohort/single cohort and high/low
routine vaccination coverage  confounding

58. CONCLUSION

59. • The results of this meta-analysis show compelling evidence of the
substantial impact of three dose girls-only HPV vaccination
programmes with the quadrivalent or bivalent vaccines on infections
by HPV 16 and 18 and HPV 31, 33, and 45 as a group, anogenital wart
diagnoses, and CIN2+ among women.
• Confirmation of evidence of herd effects among boys and older
women.
• Programmes with multi-cohort vaccination and high vaccination
coverage led to a greater and faster direct impact and herd effects.
• Next step  monitor population level impact of HPV vaccination in
low-income and middle-income countries

60. HPV VACCINATION SCENARIO IN
INDIA

61. HPV VACCINATION IN INDIA
• In Indian women, the most common prevalent genotypes are HPV-16
and 18
• Non-oncogenic HPV serotypes-6 and 11 contribute over 90% of
benign genital infections.
• Two vaccines licensed globally are available in India; a quadrivalent
vaccine (Gardasil™ marketed by Merck) and a bivalent vaccine
(Cervarix™ marketed by Glaxo Smith Kline).
• Both vaccines are manufactured by recombinant DNA technology that
produces non-infectious VLPs comprising of the HPV L1 protein

62. • Two trials of HPV vaccine were being conducted in India, a multi-centric clinical
trial evaluating the immunogenic efficacy of two doses (6 months apart) v.
conventional three doses (at 0, 2 and 6 months) of Gardasil; and another in
Khammam district(Andhra Pradesh, Gardasil) and Vadodara (Gujarat, Cervarix) to
evaluate operational feasibility of school-based and community based vaccination
for HPV vaccine.
• The state governments, Indian Council of Medical Research (ICMR) and PATH (a
US based NGO were involved in the trials.
• No biological outcome was measured in any of the trials.
• The death of four girls in Khammam caused a public outcry, which led to the
suspension of both the trials.
• Investigations by the state governments, the Drug Controller General of India
(DGCI) and ICMR found that the deaths were not related to vaccine.
• But the ban on HPV trials continue

63. INDIAN ACADEMY OF PEDIATRICS
RECOMMENDATIONS
• The Indian Academy of Pediatrics (IAP) has included the HPV vaccine in its
Universal Immunization Schedule for children.
• It has been listed as an optional vaccine that can be given to children
between the ages of 10 and 12.
• For girls older than 15 years of age, the IAP guidelines suggest that 2 doses
be given, which can be increased to 3 doses for those with weaker
immunity.
• The Indian Academy of Pediatrics Committee on Immunization (IAPCOI)
recommends offering HPV vaccine to all females who can afford the
vaccine (Category 2 of IAP categorization of vaccines).
• The vaccine should preferably be introduced to parents as a cervical
cancer-preventing vaccine and not as a vaccine against a sexually
transmitted infection.

64. THANK YOU

65. Relative risk
• Relative risk is a ratio of the probability of an event occurring in the exposed group
versus the probability of the event occurring in the non-exposed group. An example is a
relative risk of developing lung cancer (event) in smokers (exposed group) versus non-
smokers (non-exposed group). Relative risk does not provide any information about the
absolute risk of the event occurring but rather the higher or lower likelihood of the event
in the exposure versus the non-exposure group
• Relative Risk = (Probability of event in exposed group) / (Probability of event in not
exposed group)[1]
• An example will help clarify this formula.
• If we hypothetically find that 17% of smokers develop lung cancer and 1% of non-
smokers develop lung cancer, then we can calculate the relative risk of lung cancer in
smokers versus non-smokers as:
• Relative Risk = 17% / 1% = 17
• Thus, smokers are 17 times more likely to develop lung cancer than non-smokers.

66. Odds ratio
• If the disease condition (event) is rare, then the odds ratio and relative risk may
be comparable, but the odds ratio will overestimate the risk if the disease is more
common. In such cases, the odds ratio should be avoided, and the relative risk
will be a more accurate estimation of risk.
• The odds ratio compares the odds of some event in an exposed group versus the
odds in a non-exposed group and is calculated as the number of events / the
number of non-events. Stated another way, if the probability of an event is P,
then the odds ratio would be P / (1 – P). In a two-by-two table with cells a, b, c,
and d then the odds ratio is odds of the event in the exposure group (a/b) divided
by the odds of the event in the control or non-exposure group (c/d). Thus the
odds ratio is (a/b) / (c/d) which simplifies to ad/bc. This is compared to the
relative risk which is (a / (a+b)) / (c / (c+d)). If the disease condition (event) is
rare, then the odds ratio and relative risk may be comparable, but the odds ratio
will overestimate the risk if the disease is more common. In such cases, the odds
ratio should be avoided, and the relative risk will be a more accurate estimation
of risk.

68. Confidence interval
• In statistics, a confidence interval (CI) is a type of interval estimate,
computed from the statistics of the observed data, that might contain the
true value of an unknown population parameter. The interval has an
associated confidence level that, loosely speaking, quantifies the level of
confidence that the parameter lies in the interval. More strictly speaking,
the confidence level represents the frequency (i.e. the proportion) of
possible confidence intervals that contain the true value of the unknown
population parameter.
• Most commonly, the 95% confidence level is used.
• A 95% confidence interval is a range of values that you can be 95% certain
contains the true mean of the population. This is not the same as a range
that contains 95% of the values.

70. • HPV vaccines are approved for males in several countries, including
Canada, Australia, Ireland, South Korea, Hong Kong, the United
Kingdom, New Zealand, and the United States. gardasil and gardasil
9. not cervarix
• https://scroll.in/pulse/865284/efficacy-safety-cost-indias-decade-old-
debate-on-the-cervical-cancer-vaccine-erupts-again
• As of 2017, Gardasil 9® is the only HPV vaccine available in the United
States. : ACS website

74. Cross protection & herd effect
• Cross protection is a type of induced resistance developing in plants against
viruses. Its basis is that prior infection with one virus affords protection
against closely related ones.
• Cross-protection is a natural phenomenon whereby tolerance or resistance
of a plant to one virus strain is induced by systemic infection with a second.
• herd effect is defined as: "the reduction of infection or disease in the
unimmunised segment as a result of immunising a proportion of the
population". Herd immunity can be measured by testing a sample of the
population for the presence of the chosen immune parameter. Herd effect
can be measured by quantifying the decline in incidence in the
unimmunised segment of a population in which an immunisation
programme is instituted.