Protection from a Single Dose of HPV Vaccine

IARC Evidence Summary Brief No. 4

Summary

Every year cervical cancer kills nearly

350 000 women globally, 90% of whom

live in low- and middle-income countries

(LMICs). More than 95% of cervical

cancers are caused by oncogenic types of

human papillomavirus (HPV).

The vaccine against HPV is very safe

and highly eective in preventing cervical

cancer. Thus, a fundamental pillar of the

strategy to eliminate cervical cancer is

reaching the goal of vaccinating 90% of

girls with the HPV vaccine by the age of

15 years.

However, suicient and regular access

to HPV vaccines remains a signicant

challenge in LMICs. Moreover, the multiple-

dose schedule of HPV vaccination can

make vaccination programmes logistically

more complex, more expensive, and less

resilient to vaccine supply disruptions.

The optimization of the HPV vaccination

schedule is expected to improve access

to the vaccine, oering countries the

opportunity to expand the number of girls

who can be vaccinated and alleviating

the burden of the oen complicated and

expensive follow-up required to complete

the vaccination series. It is vital that

countries strengthen their HPV vaccination

programmes, expedite implementation,

and reverse the declines in coverage.

IARC has implemented studies to

accelerate cervical cancer elimination by

making HPV vaccination more eicient

and eective. These include (i) evaluating

the eicacy of single-dose HPV

vaccination, (ii) evaluating a new HPV

vaccine, and (iii) making evidence-based

projections of the public health impact of

single-dose HPV vaccination.

Introduction

In 2020, WHO launched a Global Strategy

to Eliminate Cervical Cancer as a Public

Health Problem.

That goal is supported by three key

strategic pillars, with the following

targets: primary prevention (90% of

girls aged 9–14 years vaccinated with

the HPV vaccine), secondary prevention

(70% of women screened using a high-

performance test twice in their lifetime,

by ages 35 years and 45 years, and 90%

of women with precancer treated), and

tertiary prevention (90% of women with

invasive cancer managed).

Introduction of the HPV vaccine has

been slow, particularly in LMICs but also

in high-income countries. In 2021, global

coverage with two doses was only 15%.

Reasons for the low coverage of HPV

vaccination include:

• the HPV vaccine is one of the most

expensive vaccines to be introduced in

routine immunization programmes;

• a shortage of vaccine supply forced

many LMICs to defer the planned

introduction of vaccination;

• contacting adolescent girls for the

second dose is challenging; and

• vaccine hesitancy has been

exceptionally high for this gender-

specic vaccine (girls are the priority

target population).

Major strengths of IARC’s evidence of single-dose vaccine eicacy

• Previous studies have suggested that one dose of HPV vaccine could be as eicacious

as two or three doses in healthy women. However, the small numbers of participants

highlighted the need for additional evidence to conrm the preliminary results.

• IARC conducted a large study in which 15 000 girls who received one, two, or three doses

of HPV vaccine were followed up for more than 10 years with immunological testing; aer

women were married, vaccine eicacy against persistent HPV infection was evaluated by

paired age groups.

• The strong evidence provided by this study contributed signicantly to the World

Health Organization (WHO) Strategic Advisory Group of Experts on Immunization (SAGE)

changing the recommendation on HPV vaccination to one dose (the o-label single-dose

option).

Protection from a Single Dose

of HPV Vaccine

A major public health impact

from IARC studies of vaccine eicacy

IARC Evidence Summary Brief No. 4

Evaluating the eicacy of

single-dose HPV vaccination

In September 2009, IARC initiated a

multicentre randomized trial, funded

by the Bill & Melinda Gates Foundation,

to compare the eicacy of two versus

three doses of the quadrivalent HPV

vaccine (Gardasil) in unmarried girls aged

10–18 years in India.

The trial was converted into a

longitudinal cohort study by default aer

the abrupt suspension of HPV vaccination

in any trial by the Government of India in

April 2010. By then, 4348 participants had

received three doses, 4980 had received

two doses (at 0 and 6 months), and

4949 had received one dose. Aer they

were married, vaccinated women and

a control cohort of 1484 unvaccinated

women provided samples annually for

surveillance of HPV infection. At age

25 years, vaccinated women and a control

cohort of 3500 unvaccinated women were

invited for cervical screening. Women

who were HPV-positive at screening

underwent colposcopy and biopsy.

In addition, blood samples for

immunological assays were obtained at

dierent time points (at 7, 12, 18, 24, 36,

48, and 60 months) up to 10 years aer

vaccination from a convenience sample

of vaccinated participants and a control

group of age-matched unvaccinated

women. All laboratory assays were

performed independently and in a

blinded manner.

“The outcomes of this trial are expected to improve accessibility of HPV vaccine

and improve vaccine supply, especially for LMICs.”

– Dr Partha Basu,

Early Detection, Prevention, and Infections Branch, IARC

Key evidence messages

• With one third or one half of the cost per person, policy-makers and governments can save nancial resources.

• One dose of HPV vaccine provides similar protection to that provided by two or three doses against persistent infection with HPV16 and HPV18,

the genotypes responsible for nearly 70% of cervical cancers.

• A single-dose schedule should reduce programme costs and facilitate the scaling up of HPV vaccination to improve the vaccination coverage.

• A single-dose schedule is likely to simplify logistics and make programmes more resilient by enabling multi-age catch-up and vaccination of boys.

• A single-dose schedule will probably be more acceptable to the population.

• Adequate supplies of new vaccines will be a huge step to accelerate cervical cancer elimination in LMICs and globally.

• With the three or two doses previously used per girl, a boy and a girl could now be vaccinated, increasing the herd eect and improving

programme resilience.

Call to action

Policy-makers globally should introduce HPV vaccination with

one or two doses for girls, as recommended by WHO.

Vaccine manufacturers should ensure equity in

access to HPV vaccines, particularly in LMICs.

Immunization programme managers should assess

strategies to improve HPV vaccination coverage that could

include the use of a single-dose schedule.

IARC Evidence Summary Brief No. 4

Key ndings of IARC’s single-dose

vaccine eicacy trial

The IARC study found that even aer

only one dose of vaccine, there is a high

and long-lasting immune response

10 years later. The antibody response

indicates that the protection is unlikely to

fade anytime soon. The immunological

ndings are consistent with the single-

dose vaccine’s high eicacy against

persistent HPV16/18 infections. The

results show that a single dose of the

vaccine is as eective as two or three

doses in preventing persistent HPV16

and HPV18 infections (see Figure 1).

No cases of high-grade cervical

precancers were associated with HPV16

or HPV18 in any of the vaccinated women

who underwent screening.

Evaluating a new HPV vaccine

Currently there are six licensed HPV

vaccines: three bivalent vaccines

(Cecolin, Cervarix, and Walrinvax), two

quadrivalent vaccines (Cervavac and

Gardasil), and one nonavalent vaccine

(Gardasil 9). For these vaccines, most

LMICs pay about US$ 10 per dose for

their immunization programmes, and

there is a global shortage of supply.

The Serum Institute of India has

developed a quadrivalent HPV vaccine

(Cervavac), which is likely to cost less

than previous HPV vaccines as a result

of a novel production system and local

production in India.

IARC was part of a collaboration

between the Serum Institute of India,

the Department of Biotechnology of

the Government of India, and the Bill

& Melinda Gates Foundation to design

phase II/III randomized trials to evaluate

this new vaccine and to implement the

trial at several sites in India.

The Drugs Controller General of

India, the country’s licensing authority,

agreed to license the new vaccine if its

immunogenicity could be proved to be

non-inferior to that of Gardasil with a

good safety prole.

The study, which involved girls and

boys aged 9–14 years (two-dose cohort)

and women and men aged 15–26 years

(three-dose cohort), was completed

Denitions

• Quadrivalent vaccine protects against HPV types 6, 11, 16, and 18, which cause most HPV-

associated cancers and genital warts.

• Vaccine eicacy was calculated as 1 minus the HPV infection rate in the vaccinated group,

divided by the HPV infection rate in the unvaccinated group.

• Incident infection was dened as the detection of an HPV type in any one sample.

• Persistent infection was dened as the detection of the same HPV type in two consecutive

samples taken at least 10 months apart.

• Each enrolled participant contributed once to persistent infections, once to incident

infections, or both.

• Immunogenicity is the antibody response.

“Eliminating cervical cancer is a commitment we have made and can

do. We can accelerate the timeline towards elimination by investing in

research and innovation. These important trials from IARC have helped

inform policy recommendations by

WHO and facilitate our support to

governments and other stakeholders

to eliminate cervical cancer together.”

– Dr Bente Mikkelsen,

Director of Noncommunicable Diseases, WHO

Fig. 1 Evolution of immune responses against HPV16 and HPV18 over time in the recipients of a single dose or three doses of HPV vaccine. *Blood was col-

lected from three-dose recipients at 7 months and from single-dose recipients at 12 months aer dose 1.

IARC Evidence Summary Brief No. 4

successfully. The new vaccine was

found to be highly immunogenic, and

immunogenic non-inferiority compared

to women aged 15–26 years who

received Gardasil was demonstrated in

both girls and boys against the targeted

HPV types. The safety prole was also

comparable to that of Gardasil. Aer

reviewing the study outcomes, the

Indian regulators approved marketing

authorization for the new vaccine for

females and males aged 9–26 years.

An approval by the Drugs Controller

General will enable the Government

of India to procure enough doses of

HPV vaccine produced by the Serum

Institute of India because nearly

50 million girls aged 9–14 years in India

are waiting to receive the vaccine. The

introduction of the new HPV vaccines

that have recently been developed

(Cervavac, Cecolin, and Walrinvax) will

be a huge step to accelerate cervical

cancer elimination in India and globally,

and an option to improve access and

aordability.

Evidence-based projections of the

public health impact of single-dose

HPV vaccination

IARC projected the health benets

and potential economic impact of a

national single-dose HPV vaccination

programme for girls in India. The

study found that such a vaccination

programme could substantially reduce

the incidence of cervical cancer, to

below the incidence rate established

by WHO as the threshold for the

elimination of cervical cancer as a

public health problem (see Figure 2).

If HPV vaccination is introduced now,

it could prevent almost 1 million cases

of cervical cancer over the lifetime of

the birth cohort currently aged 10 years

or younger. This study complements

existing evidence that single-dose

HPV vaccination could be an eective,

eicient, and cost-eective strategy for

cervical cancer prevention in India and

other LMICs.

This mathematical economic modelling

study showed that the introduction of

single-dose HPV vaccination in India

is likely to be cost-eective. Two-dose

vaccination would have a less favourable

cost–eectiveness prole. These results

“With the new safe, highly eective, and aordable

vaccine, LMICs are on the way to universalizing

national-level HPV vaccination programmes.”

– Professor Neerja Bhatla,

Past Chair of Women’s Cancer Committee, FIGO

Fig. 2 Projected impact of single-dose HPV vaccination of girls on cervical cancer incidence in India.

Current WHO HPV vaccine recommendations (2022):

IARC Evidence Summary Brief No. 4

could be used by health oicials in the

Indian government in their decision-

making on the introduction of HPV

vaccination and could convey several

lessons for implementation in other

LMICs.

New WHO recommendations

In April 2022, WHO SAGE evaluated the

evidence that has recently emerged

that single-dose schedules provide

comparable eicacy to two-dose or

three-dose schedules.

The WHO SAGE review concluded that

a single-dose HPV schedule delivers solid

protection against HPV, comparable

to that of a two-dose schedule. WHO

advised that countries may now choose

between a one-dose or two-dose

schedule for girls aged 9–14 years.

Implications: early policy

changes aer the new WHO

recommendations

IARC studies contributed signicantly to

the new single-dose recommendation

from WHO, and countries in all parts

of the world are planning to switch or

have already switched to a one-dose

schedule, including Albania, Australia,

Cabo Verde, Ireland, Mexico, Solomon

Islands, Tonga, and the United Kingdom.

Several National Immunization

Technical Advisory Groups in GAVI-

eligible countries have already

recommended a single-dose schedule

and may soon introduce HPV

vaccination, including in Bangladesh,

India, and Nigeria.

Acknowledgements

Indian citizens who participated in the Evaluation of the eicacy of single-dose HPV vaccination trial, and Indian investigators and collaborators

involved in this study from Gujarat Cancer & Research Institute, Ahmedabad; Christian Fellowship Community Health Centre, Ambilikkai; Nargis

Dutt Memorial Cancer Hospital, Barshi; Mehdi Nawaj Jung Cancer Institute Hyderabad; Cancer Foundation of India, Kolkata; Civil Hospital, Aizawl,

Mizoram; Tata Memorial Centre, Mumbai; All India Institute of Medical Sciences, New Delhi; Jehangir Clinical Development Centre, Pune; Sir Thodup

Namgyal Memorial Hospital, Gangtok, Sikkim; and Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram.

We are very grateful to the Bill & Melinda Gates Foundation for their generous nancial support, and to the European Commission Seventh

Framework Programme grant HPV-AHEAD (FP7-HEALTH-2011-282562) for partial support for the establishment of the laboratory at Rajiv Gandhi

Centre for Biotechnology, Thiruvananthapuram, India.

Rengaswamy Sankaranarayanan, former Principal Investigator; Partha Basu, Principal Investigator; Richard Muwonge, co-Investigator; Eric Lucas,

co-Investigator; Tarik Gheit, co-Investigator; Iacopo Baussano, co-Investigator; Irene Man, co-Investigator; International Agency for Research on

Cancer, Lyon, France.

Key references

Joshi et al. (2023). Vaccine. 41(1):236–45. PMID:36446654

Man et al. (2022). Lancet Oncol. 23(11):1419–29. PMID:36174583

Basu et al. (2021). Lancet Oncol. 22(11):1518–29. PMID:34634254

tivecommons.org/licenses/by-nc-nd/4.0/) (p. 3, top), © WHO/PAHO (p. 3, bottom), compiled from Man et al. (2022), published by Elsevier Ltd (p. 4, top)

The mention of specic companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO or

contributing agencies in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary

products are distinguished by initial capital letters.

For more information about HPV vaccine trials, please email b[email protected]

To cite this Brief

IARC (2023). Protection from a Single Dose of HPV Vaccine: A major public health impact from IARC studies of vaccine eicacy (IARC Evidence

Summary Briefs, No. 4). Lyon, France: International Agency for Research on Cancer. Available from: https://www.iarc.who.int/evidence-summary-

briefs-series/.

For information on the IARC Evidence Summary Briefs series, please email evidencebriefseries@iarc.who.int

April 2023

@IARCWHO

“These recommendations will pave the way for

more girls and women to be vaccinated and thus

prevent cervical cancer.”

– Professor Rakesh Aggarwal,

WHO SAGE member