Literature review on HPV 6, 11, 16 and 18: Disease and Vaccine Characteristics

June 2007

¹ Field Epidemiologist, Canadian Field Epidemiology Program, Public Health Agency of Canada
² Clinical Associate Professor, Vaccine Evaluation Centre, University of British Columbia
³ Senior Medical Specialist, Immunization and Respiratory Infections Division, Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada

(full PDF version 366 KB)

This review was commissioned by the Public Health Agency of Canada (PHAC).

Table of Contents

1. Acronyms & Glossary
2. Introduction
3. Methods
4. Results
   
   • IV.1 Burden of disease caused by HPV 6, 11, 16 and 18
     Table 1: HPV positivity (all genotypes, 16 and 18) for selected cancers and precancerous lesions worldwide
     Table 2: Other risk factors associated with cervical cancer
     
   • IV.2 HPV Vaccines, Gardasil™ and Cervarix™
     1. Nature and characteristics of immunizing agent
     2. Characteristics of the commercial products and administration schedule
     3. Vaccine manufacturers, production capacity and supply to Canada
     4. Nature and characteristics of immune response
     4.1 General overview
     4.2 Immunoassays to measure anti-HPV antibodies
     4.3 Induction of immunity to HPV VLPs in the female genital tract
     4.4 Description of HPV Vaccine Phase II and III Trials
     Table 3: Comparison of trial protocols for the Merck and the GSK products
     Table 4: Vaccine trials and source publications
     4.5 Immunogenicity of HPV Vaccines in Phase II and III studies
     Table 5: Geometric Mean Titres and Seropositivity from Monovalent HPV 16 Vaccine (Merck product), Gardasil™ and Cervarix™
     5. Immunogenicity in other populations
     Table 6: GMTs in girls, boys and women at t=7 months following vaccination with Gardasil™
     Table 7: GMTs at t=7 months following vaccination with Cervarix™ in younger and older female age groups
     6. Short and long-term vaccine efficacy against persistent infection and disease
     6.1 Trial of HPV 16 L1 VLP, Merck product
     6.2 Trials of Gardasil™
     6.3 Trials of Cervarix™
     Table 8: Vaccine efficacy against infection or disease from HPV viruses covered by the vaccine
     7. Effect of the vaccine on the transmission of the type-specific and related HPV genotypes
     8. Short and long-term population effectiveness (i.e. impact on reduction of burden of disease, including herd immunity)
     Table 9: Vaccine efficacy of Cervarix™ and Gardasil™ in HPV naïve and general populations
     9. Vaccine safety and adverse events
     Table 10: Common adverse events reported in the vaccine trials and product monograph
     Table 11: Causes of death among participants in the Gardasil™ trials
5. Discussion
6. Acknowledgments
7. References

I. Acronyms & Glossary

ACIP	The Advisory Committee on Immunization Practices
ADC	Adenocarcinoma
AGC	Atypical glandular cells
AIS	Adenocarcinoma in situ
ASC-H	Atypical squamous cells, cannot exclude high grade
ASCUS	Atypical squamous cells of undetermined significance
ASO4	Adjuvant containing 500 μg aluminum hydroxide and 50 μg 3-deacylated monophosphoryl lipid A
Baculoviruses	Viruses that attack insects and other arthropods
Capsomeres	Protein units that make up the viral capsid or outer shell
CI	Confidence interval
CIN	Cervical intraepithelial neoplasia; this is subclassified into threecategories (CIN 1, CIN 2, and CIN 3)
CIS	Carcinoma in situ
cLIA	competitive Luminex based Immunoassay
cRIA	competitive Radio Immuno Assay
DNA	Deoxyribonucleic acid
ELISA	Enzyme-Linked Immunosorbent Assay
Epitope	a molecular region on the surface of an antigen capable of eliciting animmune response and of combining with the specific antibodyproduced by such a response (also known as determinant or antigenicdeterminant)
FUTURE	Females United to Unilaterally Reduce Endo/Ectocervical Disease
GMT	Geometric mean titres
GSK	GlaxoSmithKline
HR	High-risk (carcinogenic) HPV viruses: 16, 18, 31, 33, 35, 39, 45, 51,52, 56, 58, 59
HSIL	High grade squamous intraepithelial lesion (CIN 2,3)
HPV	Human papillomavirus
IARC	International Agency for Research on Cancer
Icosahedral	A structure with twenty sides
IL	Interleukin
IM	Intramuscular
INF	Interferon
ITT	Intention-to-treat
LR	Low-risk (non-carcinogenic) HPV viruses: 6, 11, 40, 42, 43, 44, 54, 61,70, 72, 81, CP6108
LSIL	Low-grade squamous intraepithelial lesion (CIN 1)
MITT	Modified intention-to-treat
MPL	Monophosphoryl lipid A
NA	Not available
NACI	The National Advisory Committee on Immunization
NOCD	New onset chronic disease
OCP	Oral contraceptive pills
OR	Odds ratio
PATRICIA	PApilloma TRIal against Cancer in young Adults
Pentamer	A molecule composed of five monomeric units
Prophylactic vaccine	These vaccines are designed to protect an individual against an initialinfection; thus the vaccines are given pre-exposure
Pseudovirion	A synthetic virus that is similar in structure and characteristics to anatural virus except that it lacks the capacity to replicate
PHAC	The Public Health Agency of Canada
RCT	Randomized, placebo-controlled trial
RRP	Recurrent respiratory papillomas
Saccharomyces cerevisiae	Baker’s or brewer’s yeast, also known as the ‘top’ fermentor
SCC	Squamous cell carcinoma
Therapeutic vaccine	These vaccines are designed to treat an existing infection thus aregiven post exposure
trichnoplusia ni	Commonly called the cabbage looper, a pest of plants such ascabbage, broccoli, cauliflower, Chinese cabbage
VaIN	Vaginal intraepithelial neoplasia
VIN	Vulvar intraepithelial neoplasia
VLP	Virus like particles

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II.Introduction

In 2006, the first of two vaccines for human papillomavirus (HPV) prevention, Gardasil™, was approved for use in Canada. Gardasil™, produced by Merck Frosst Canada Ltd, is a quadrivalent vaccine product against HPV 6, 11, 16 and 18. The National Advisory Committee on Immunization (NACI) statement on the recommendations for the use of HPV vaccine for the prevention of cervical cancer was released in January 2007¹. A second HPV candidate vaccine, Cervarix™, produced by GlaxoSmithKline (GSK) Inc in Belgium is currently undergoing the regulatory review process by Health Canada. This is a bivalent vaccine against HPV 16 and 18. A need for a systematic literature review on the characteristics of the HPV vaccines was identified. This review was commissioned by the Public Health Agency of Canada (PHAC).

The purpose of this document is to apply the Erickson, De Wals and Farand framework2 on immunization programs to review the following:

• the disease burden attributed to HPV 6, 11, 16, and 18; and to identify non-HPV risk factors for cervical cancer; and
• the vaccine characteristics of Gardasil™ and Cervarix™.

Literature review on HPV 6, 11, 16 and 18: Disease and Vaccine Characteristics
M Dawar¹, S Dobson², S Deeks³
(full PDF version 366 KB)