Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

7th Canadian Immunization Conference

Winnipeg, Manitoba / December 3-6, 2006

The burden of illness directly attributable to infection by human papillomavirus (HPV) is onerous. At the most serious end of the spectrum is cancer, including cervical cancer, approximately 70% of which is caused by HPV, as well as about half of all vulvar, vaginal and penile cancers, and some 20% of all oropharyngeal cancers. Indeed, the link between the high-risk oncogenic subtypes of HPV, namely 16 and 18, and cervical cancer is the strongest for any type of cancer and infectious agent, noted Dr. Wylam Faught, Professor and Chair of Obstetrics and Gynecology, University of Alberta, Edmonton. HPV also causes both high- and low-grade cervical dysplasias as well as anal and genital warts in men and women. Some 90% of all genital warts are also caused by HPV subtypes 6 and 11, with up to 80% of young women being infected with HPV within two to three years following sexual debut. Once young patients develop genital warts, the psychological sequelae can be very high, as are both diagnostic and treatment-associated costs of clinical manifestation of HPV infection.

As discussed by Dr. Deborah Money, Associate Professor and Head, Division of Maternal Fetal Medicine, British Columbia Women’s Hospital and Health Centre, Vancouver, the mean age of first intercourse in Canada is 15.7 years, “which means that young adults have had skin-to-skin contact and exposure to HPV when they are around 13 years old.”

In Canada, approximately 1350 new cases and 390 deaths due to invasive cervical cancer are estimated for 2006. The availability of a prophylactic HPV vaccine offers an opportunity to reduce or eliminate precancerous cervical changes caused by HPV infection. Immunization with the quadrivalent vaccine, both prior to sexual debut and in those already exposed to the virus, would greatly reduce, if not eliminate, genital warts from HPV subtypes 6 and 11. The quadrivalent vaccine containing subtypes 16, 18, 6 and 11 is currently approved for use in females between the ages of nine and 26.

Published data on results evaluating the vaccine indicate that it has very high immunogenicity rates—“many-fold higher than natural immunity,” Dr. Money noted. These high immunogenicity rates were shown to protect vaccine recipients against all HPV-related disease due to strains in the vaccine at the end of the three-year randomized trial, as well as against all but transient infection with HPV. Based on combined data from four clinical trials evaluating the quadrivalent vaccine, there were no new cases of HPV 16- or 18-related cervical intraepithelial dysplasia (CIN) 2/3 among vaccine recipients at the end of three years vs. 53 for placebo controls (100% vaccine efficacy). There was one case of HPV-related genital warts vs. 91 cases for placebo controls, representing a 98.9% efficacy rate. Ongoing investigation with the bivalent HPV vaccine containing HPV subtypes 16 and 18 has similarly demonstrated very high immunogenicity rates in young women, suggesting that it, too, will reduce or eliminate HPV 16- and 18-related high- and low-grade cervical changes and associated cervical cancer.

As Dr. Money cautioned, these vaccines work very well against HPV types contained in the vaccines but they do not protect patients against disease caused by non-vaccine subtypes: “They do not eliminate every aspect of HPV-related disease.” She also stressed that because these vaccines will protect women against only about 70% of cervical cancers, women must continue to undergo regular Pap screening even if use of the HPV vaccine does become routine. Nevertheless, these prophylactic vaccines represent the first real opportunity in gynecological medicine to prevent cervical cancer in a large majority of women, something that has never before been available, as Dr. Money indicated. “The huge benefit to these vaccines is going to be on preventing precursors to cervical cancer which result in the stress of abnormal Pap smears, colposcopy and sometimes ablative therapies and removal of parts of the cervix, while the vaccine that holds HPV types 6 and 11 will hopefully have the ability to prevent genital warts, which have substantive psychosocial issues for patients,” Dr. Money told delegates. “If we can get young girls prior to sexual exposure and have them all vaccinated, we can really impact on the burden of disease, at least for the vaccine-containing types.”

A cost analysis of the quadrivalent HPV vaccine also shows that it should prove highly cost-effective within the Canadian health care setting. As presented by Dr. Marc Brisson, Canada Research Chair in Mathematical Modeling and Health Economics, Université Laval, Quebec City, the model used by his group indicated that HPV 6, 11, 16 and 18 cause 36,000 new cases of genital warts in Canada each year, 74,000 cases of CIN, 800 cases of cervical cancer and 320 deaths from cervical cancer. The mathematical model also showed that cost of vaccinating 12-year-old girls with the quadrivalent vaccine was less than $15,000 for each quality-adjusted life-year gained, “well below the $50,000 threshold at which interventions are deemed cost-effective,” he noted.

The same mathematical model also found the number needed to vaccinate (NNV) to prevent one episode of genital warts was eight, while the NNV to prevent one CIN 1 was 14 and 31 to prevent one CIN 2/3. (NNV is calculated as the number of women [within a specific age cohort] that are needed to be vaccinated with a quadrivalent [HPV type 6, 11, 16 and 18] vaccine to prevent an HPV-related event during their lifetime.) Some 276 12-year-old girls would have to be vaccinated to prevent one cervical cancer, while 639 would need to be vaccinated to prevent one cervical cancer death.

Rotavirus Vaccine

The new rotavirus vaccine should have a similarly major impact on disease burden in young infants. As discussed by Dr. Umesh Parashar, Team Leader, Respiratory and Enteric Viruses, Centers for Disease Control and Prevention, Atlanta, Georgia, an estimated 50,000 to 70,000 hospitalizations due to rotavirus occur each year in the US alone. (In Canada, hospitalization rates range from one out of 62 to one out of 106 children infected with rotavirus, with the average length of stay ranging from two to three days.)

Efficacy results demonstrated that the rotavirus vaccine (currently available in Canada) reduced hospitalizations by 96%, emergency room visits by 94% and outpatient visits by 86%. The rotavirus vaccine is shown to be 98% effective in preventing severe rotavirus gastroenteritis and 74% effective in preventing rotavirus of any severity. “The vaccine will have a tremendous impact on reducing events from rotavirus in all settings,” Dr. Parashar confirmed. The same trial also revealed how important a role the rotavirus vaccine plays in gastroenteritis in young children, as hospitalizations for gastroenteritis from all causes were reduced by almost 59% in vaccine recipients compared with placebo controls. “As a parent, I can vouch that rotavirus infection is not a pleasant illness,” remarked Dr. Parashar. Not only is the diarrhea troublesome, but it is usually accompanied by frequent vomiting and fever, which makes maintenance of good hydration very difficult, he added.

Dr. Lee Ford-Jones, Professor of Pediatrics, University of Toronto, similarly underscored the importance of parents knowing how to keep their sick child rehydrated: they need teaspoons or tablespoons of fluid every few minutes. “Frequent hand-washing has also been shown to reduce diarrhea rates by 50%,” she added. Members of the National Advisory Committee on Immunization are working towards a statement on implementation of the licensed rotavirus vaccine across the country but the vaccine is available now if parents express a desire for their child to be vaccinated against infection. “There is no question that rotavirus is a hugely important cause of infant and toddler diarrhea and that it extends to other family members as well,” Dr. Ford-Jones noted. However, because a previously licensed rotavirus vaccine was associated with an increased risk of intussusception, “a higher demand is being put on this vaccine than ever before. We have to make sure this vaccine is perfectly safe.”

Herpes Zoster

Whether or not widespread use of the varicella vaccine in young children will affect long-term reactivation of the virus in adults is not known, but it appears that the incidence of herpes zoster will indeed increase as adults are no longer “boosted” by exposure to chickenpox in children.

As explained by Dr. Allison McGeer, Professor of Laboratory Medicine, Pathobiology and Public Health Sciences, University of Toronto, Ontario, there is now substantial evidence that cumulative lifetime rates of herpes zoster, currently between 25 and 35%, are actually relatively low because adults are often exposed to children who have chickenpox and this exposure helps boost their immunity to the varicella virus. In one study cited by Dr. McGeer, for example, adults living in households with children under the age of 16 reduced their risk of developing herpes zoster by 25%, “and if you live in a household with children who have a history of chickenpox, it reduces herpes zoster risk even further,” Dr. McGeer noted.

This suggests that as rates of primary varicella drop as a result of widespread varicella vaccination programs, “the risk of zoster is going to go up because people do not get that boosting,” she added, with lifetime risk increasing to approximately 50% in the foreseeable future. Consequently, adults will need even greater protection against herpes zoster than they now do, Dr. McGeer observed. Current treatments for acute zoster include acyclovir, valacyclovir or famciclovir, given for seven to 10 days within 72 hours of rash onset, all of which appear to halve the incidence of post-herpetic neuralgia (PHN). First-line treatment for PHN included analgesics, tricyclic antidepressants, gabapentin or pregabalin, but speakers here concurred that treatments for herpes zoster and PHN are far from ideal. Prevention of herpes zoster and its feared complications is obviously a preferred strategy, Dr. McGeer indicated.

Results from the Shingles Prevention Study (SPS) carried out in approximately 39,000 participants 60 years of age and older showed that the burden of illness due to herpes zoster three to five years after receipt of the vaccine was 61.1% lower in those who received a single dose of the live attenuated Oka/Merck varicella zoster vaccine compared with placebo controls, while the incidence of PHN and herpes zoster was between 50 to 60% lower. Vaccine efficacy was significantly lower in recipients aged ³70 years than in those between the ages of 60 and 69, Dr. McGeer reported, but there was no difference in the burden of illness scores or the incidence of PHN between the two age groups, suggesting that the vaccine attenuates disease severity in older recipients when zoster does occur.

“Boosting by natural exposure or by vaccine will significantly reduce the incidence and severity of herpes zoster in older adults, so we need to look at vaccination of adults as a replacement and hopefully improvement on natural boosting to reduce the incidence and severity of zoster in populations in the future,” Dr. McGeer concluded.

Meningococcal Serogroup C Vaccine

The introduction of the meningococcal serogroup C conjugate vaccine in the UK was a highly successful program and proved highly informative for public health officials. As reviewed by Dr. Elizabeth Miller, Health Protection Agency, Centre for Infections, London, UK, three meningococcal vaccines became available in 2000 and the strategy was to introduce them routinely, in a three-dose schedule, at two, three and four months of age, as well as in a catch-up program for children up to 18 years of age.

In previous years, there was always a “marked winter peak” of meningococcal disease in the 15-, 16- and 17-year-olds where carriage rates are highest, noted Dr. Miller. Following introduction of the vaccine, “the rate [of meningococcal disease] immediately plateaued,” she reported, “and this was the first evidence that this vaccine was going to be highly effective.” Indeed, there has been a progressive decline in meningococcal C disease in all age groups since the introduction of the vaccines, even among those over the age of 20, because of herd immunity.

As Dr. Miller also noted, public health officials were somewhat concerned that successful eradication of group C meningococcal disease might result in serogroup replacement with B disease. This has not proven to be the case, as there has been a progressive decline in both B and C meningococcal disease across England and Wales. Also of interest, vaccine efficacy proved to be very high among infants immunized at two, three and four months of age within the first year, but protection declined markedly after one year. In contrast, there was some decline in vaccine efficacy in older age groups but protection rates did not differ significantly over time. Yet as Dr. Miller indicated, young infants are still not developing meningococcal disease because carriage rates have essentially been eliminated in the population.

Varicella Vaccine

As reviewed by Dr. Jane Seward, Centers for Disease Control and Prevention, prior to the introduction of the varicella vaccine, the average number of varicella cases in the US was around four million a year, which necessitated between 11,000 and 13,500 hospitalizations each year and caused between 100 and 105 deaths. Following introduction of the varicella vaccine in 1996, vaccine coverage has gone from 26% in 1997 to 88% in 2005, with no gaps in uptake according to either race or ethnicity. In fact, 44 states now make varicella vaccination coverage a requirement for childcare and elementary school entry, she noted.

Some 47 million doses later, there have been no deaths attributable to the vaccine itself and serious adverse events are very rare: when they do occur, they usually unmask an underlying immunocompromising condition, Dr. Seward explained. Pregnancy registry data confirm there have been no episodes of congenital varicella syndrome in women exposed to the vaccine during pregnancy and major birth defects in children born to mothers exposed to the vaccine are similar to background rates. Post-licensure experience also shows that the vaccine prevents 99% (mean) of severe varicella—100% median—“so it is highly effective against severe disease,” Dr. Seward observed. “We are seeing excellent disease control with one dose in the varicella vaccination program in children and we anticipate improved disease control with the two-dose program.”

Dr. Marian MacLellan, School of Nursing, St. Francis Xavier University, Antigonish, Nova Scotia, examined a group of Canadian parents’ reasons for whether they would have their child immunized against varicella. In June 2005, 148 parents with children between the ages of one and five were asked if they had had their children immunized; sixty-two per cent of parents indicated they had not (Nova Scotia funded the varicella vaccine program in 2003 so public funding was not an issue). “The number one reason for not immunizing their child was that they already had varicella,” Dr. MacLellan noted. But a significant proportion of the parents reported that they did not have their child immunized because the vaccine was not free (16%) or that their physician did not recommend it (10%). Over half (56%) indicated they did not see varicella as a serious disease.

“Varicella should not be a ‘rite of passage’—it is a vaccine-preventable disease and parents look to health care providers for advice on immunizations and the rationale for new vaccines,” Dr. MacLellan concluded.