The Advisory Committee on Immunization Practice (ACIP) met in Atlanta, GA, on October 25–26, 2011. Complete minutes of the meeting will be published on the CDC National Center for Immunization and Respiratory Diseases (NCIRD) website.
Human papillomavirus vaccine
Quadrivalent human papillomavirus (HPV4) vaccine (Gardasil—Merck) was approved in 2006 for use in patients aged 11 to 26 years. HPV2 (Cervarix—GlaxoSmithKline) was introduced in 2009 for ages 10 to 26 years, and at the same time, HPV4 was approved for use in males aged 9 to 26 years. Many previous sessions have been presented at ACIP on the efficacy and safety of HPV vaccine.
Current U.S. vaccine safety surveillance data were presented. According to data from the Vaccine Safety Datalink project, female patients have received more than 600,500 doses of HPV4 from August 2006 to October 2009. No statistically significant increase has occurred in preselected adverse events (i.e., Guillain–Barré syndrome, stroke, venous thromboembolism [VTE], appendicitis, seizures, syncope, allergic reactions, anaphylaxis). A nonstatistical increase was seen in the number of VTE events (eight cases, with only five meeting standard case definition). All five cases had other risk factors for VTE. A total of 12 confirmed cases of anaphylaxis have been reported, and all patients were treated and recovered. Syncope was reported at a rate of 15.3 cases per 10,000 population, which confirms the need to monitor patients following vaccination.
Another safety review was performed by Kaiser Permanente among 189,629 female patients who had received one or more doses of HPV4. These females ranged in age from 9 to 26 years, with the exception of about 1,700 who were outside the range (i.e., mostly older). This study sample was divided into primary safety, autoimmune population, and pregnant population groups. No pattern of birth anomalies or miscarriages was observed other than that which would be suspected in the general population. The investigators also determined that no evidence of autoimmune disease caused by vaccination existed. In the general safety review, syncope is associated with vaccination, usually at time of vaccination. Although a slight relationship existed between local skin infections and vaccination, the skin infections could have resulted from injection site reactions.
An estimated 7,080 cancers related to HPV types 16 and 18 occur each year in males (14,720 in females). In males, incidence of oropharyngeal, anal, and penile cancers is increasing. (Anal cancer is increasing by 2.7% per year.) From 1988 to 2004, a 28% increase occurred in oropharyngeal cancers, with HPV-associated oropharyngeal cancers increasing by 225% during that time. HPV vaccine safety trials were reviewed and demonstrated high efficacy and safety, including data in males (HPV4). Follow-up studies for duration of action range from 3 to 8.5 years, and immune memory has been demonstrated. Follow-up will continue for 10 years.
Overall coverage of HPV vaccine is 48.7% for more than 1 dose and 32% for three or more doses. More than 30% of parents surveyed stated that they would not get the HPV vaccine for their child or were not sure whether they would get it. Also, surveys of acceptability of vaccination of males showed strong support because the transmission of HPV by males to females justifies male vaccination. Very few survey respondents felt that vaccinating females only was the best policy.
Cost effectiveness of male HPV vaccination depends on the level of female vaccination. Cost per quality-adjusted life year gained for males is $23,600 with female coverage at 20% and $184,300 with 75% coverage of females. Increasing female coverage is actually more cost effective. Also, cost effectiveness decreases with age, making it important to vaccinate at age 12 years.
Taking all of this into consideration, the ACIP working group favored routine vaccination in males and females. The final vote stated the following: “ACIP recommends routine vaccination of males aged 11–12 years with 3 doses of HPV4. The vaccination series can be started beginning at age 9 years.”
The second discussion was regarding the age of vaccination. Consideration was given to lowering the age of routine vaccination to 21 years and making 22 to 26 years permissive. ACIP felt that harmonization should occur between male and female recommendations. The recommendation is as follows: “Vaccination is recommended for males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose series. Males aged 22 through 26 may be vaccinated. Priority should be given to males aged <22 years as vaccination of young men and boys would provide the greatest benefit.”
In addition, HPV vaccine is recommended for men who have sex with men through age 26 years and for immunocompromised (including HIV-infected) males.
Childhood and adolescent vaccine schedules
The childhood and adolescent HPV immunization schedules are slated to be published in February 2012. The basic layout of the schedules will not change. The footnotes for the schedule for children aged 0 to 6 years schedule have been condensed and revised to save space. Also, a change was made to reflect the licensure of Menactra (sanofi pasteur) to age 9 months. For the live attenuated influenza vaccine (LAIV) footnotes, contraindications were added and the wording edited to reflect changes in the two-dose recommendation of influenza vaccine to children younger than 9 years (see influenza discussion below).
The footnotes for the schedule for patients aged 7 to 18 years have been revised and condensed. This schedule also will be modified to reflect the changes to HPV vaccine recommendations during the ACIP meeting described here. In addition, the 16-year dose of meningococcal vaccine was added.
The catch-up schedule was revised to reflect the above changes.
Adult vaccine schedules
There will continue to be two adult vaccine schedules based on age and medical conditions, and the schedules will be published in February 2012. Again, footnotes have been clarified and condensed. Changes to tetanus–diphtheria–pertussis (Tdap) vaccine in pregnancy and adults older than 65 years were added. Also, HPV vaccine recommendations to health care providers were clarified to indicate that the vaccine is only recommended if the provider is in the regular age group for HPV vaccination. An additional clarification is that meningococcal vaccination is recommended for individuals up to 21 years of age who live in residence halls if they have not had a dose at 16 years.
Hepatitis B vaccination of patients with diabetes
A review of incidence of hepatitis B from eight emerging infection program sites demonstrated 865 cases. Of those hepatitis patients, 11% (n = 95) had diabetes. When further divided, 68 of 756 hepatitis patients (9%) were aged 23 to 59 years and 27 of 109 (24.8%) were older than 60 years. The sites also reported that 19.5% of patients with diabetes and 34.6% of patients without diabetes had other risk factors for hepatitis B. The adjusted odds ratio for patients with diabetes having hepatitis B was 2.09 for patients aged 23 to 59 years and 1.45 among those older than 60 years. In summary, compared with people without diabetes, individuals with diabetes have a twofold higher risk for hepatitis B at age 23 to 59 years and a 1.5-fold higher risk at greater than 60 years.
Studies also revealed that the immune response (or vaccine efficacy) of the hepatitis B vaccine, along with all vaccines, was much better, as well as more cost effective, when given at a younger age. It was not cost effective after age 60 years.
ACIP voted to recommend hepatitis B vaccination to adult patients with diabetes who are younger than 60 years (routine). Also, hepatitis B vaccination may be administered to unvaccinated adults with diabetes who are older than 60 years (permissive).
Discussion focused on routine use of meningococcal vaccine among infants. There are three vaccines licensed or under development. MenACWY-D (Menactra) is licensed in infants at aged 9 to 23 months patients aged 2 to 55 years. MenACWY-CRM (Menveo—Novartis) is licensed for patients 2 to 55 years of age and is under evaluation for infants at ages 2, 4, 6, and 12 months. HibMenCY-TT (MenHibrix—GlaxoSmithKline) is under FDA review for infants at ages 2, 4, 6, and 12 months. The vaccines under review are safe and immunogenic. In addition, no interference occurred when the vaccines were given with seven-valent pneumococcal conjugate vaccine (PCV7; Prevnar 7—Pfizer).
Rates of meningococcal disease have fallen to about 0.5 cases per 100,000 population. Knowing that the disease is cyclical, we could be in the midst of a low season. Although the incidence of disease in infants is higher than other age groups, serotype B is seen in about 50% of cases (not covered in vaccine). Serotype B is lower in older age groups. Meningococcal disease ranges from 77 cases/year in low-incidence years, to 222 cases/year in moderate-incidence years, and to 475 cases/year in high-incidence years. Although incidence of the disease is lower, the severity is high. Cost-effectiveness data were again discussed. In the past, the working group felt that infant vaccination against meningococcal disease could not be recommended. As the prices of the new vaccines are unknown, the cost effectiveness could change. Again, the working group felt that the incidence of disease is too low to make a routine recommendation at this time. However, there may be high-risk groups or an outbreak, which would suggest that vaccination is needed. The working group will continue to assess the situation.
Pfizer has applied to FDA for Prevnar 13 (PVC13) use in adults 50 years or older, and it is anticipated to be approved by January 1, 2012. PCV13 is indicated for the prevention of the 13 pneumococcal serotypes included in the vaccine. In one trial among patients older than 60 years, PCV13 was given 1 year after the 23-valent polysaccharide vaccine (PSV23; Pneumovax 23—Merck) and to PSV23-naive patients. If given following PSV23, a rise in antibody titers was observed, but not as high as two doses of PCV13 (for the serotypes in the vaccine). If PCV13 was given followed by a second dose of PCV13, a higher booster effect was seen if no PSV23 was given previously.
The policy question is whether ACIP should recommend PCV13 for immunocompromised adults. Current pneumococcal vaccination policy was stated. Immunocompromised patients, especially those with asplenia, HIV, and cancer, and transplant patients have a much higher incidence of pneumococcal disease. The working group recognizes that the burden of disease and opportunities for prevention beyond PSV23 should be evaluated. The working group will continue reviewing the data in order to reach a conclusion when the vaccine is licensed.
Vaccines and febrile seizures
A follow-up of the general recommendation working group was presented. As presented at the previous ACIP meeting, a slight increase was seen in the 2010–11 influenza season with the concomitant administration of trivalent influenza vaccine (TIV) and PCV13. This risk was seen in children aged 12 to 23 months who received a first dose of TIV plus PCV13. Risk was 61 cases per 100,000 population or 1 febrile seizure case in 1,640 vaccinees. An updated review of the data revealed no changes since last presentation. ACIP continues to recommend that both vaccines be given together if indicated. Because these data were presented after the general recommendations were published, this particular recommendation did not make it to press. Other issues not in the general recommendations include contraindication and precaution changes, administration, and vaccination records. The working group will address these topics in the future.
Pertussis continues to be an issue in most communities. ACIP has made several recent recommendations regarding Tdap use. FDA approved Boostrix (GlaxoSmithKline) for patients older than 65 years, with the following policy update in September recommending vaccination in this age group. Additional recommendations were made in October to include an indication for pregnant women. The working group is reviewing these recommendations and is looking at the epidemiology among older individuals. Tdap revaccination will be discussed at the ACIP meeting in February 2012.
Measles cases continue to increase in the United States, with the latest count indicating 214 cases in 2011. Of these cases, 26% have occurred in adults older than age 20 years, 25% in children younger than 12 months, 7% in children 12 to 15 months (recommended age for measles vaccination), and the rest in individuals aged 1 to 19 years. More than 85% of these measles cases have been unvaccinated or had an unknown vaccination status. The vaccination status was unknown for most patients in the group older than 20 years. Investigating these cases cost between $5,000 and $167,000 per case. Most of the cases were importation or importation related. The challenge is that measles incidence remains high in western Europe and the risk of importation is high.
Currently, a large outbreak of measles is occurring in Quebec, Canada. Since 1996, Canada has had a two-dose vaccination series (measles–mumps–rubella) given at 12 and 18 months. Most of the current cases are related to the 28,000 cases occurring in Europe in 2011. (France had 14,500 cases.) Since April 2011, Quebec has reported 745 confirmed cases. The majority of the cases were unimmunized; however, 15% to 20% of the adolescents had received two doses. In one study of a school outbreak, 4.8% had been vaccinated with two doses and 82% were unvaccinated. Several attenuated cases were determined by lab report, which demonstrated that the patients were exposed and their antibody levels from vaccination increased, along with a mild rash. In the study, vaccine effectiveness was calculated to be 94.2% overall. This demonstrated that a very high rate of measles vaccination must be maintained and that vaccination effectiveness is not perfect.
Last, the use of measles vaccine in patients with HIV was discussed. As a result of new information, the working group is evaluating whether its recommendations should be modified. A vote did not occur at the meeting.
Influenza activity is very low currently, and all three virus strains (H1N1, H3N2, and B) are circulating.
The following vaccine efficacy estimates were based on four sites around the United States:
Of note, the characteristics of the study samples varied at each of the four sites. Data at each of the four sites were too few to make vaccine efficacy estimates for each site. Also, serological data were not available to determine whether vaccine failures occurred. Last, the type of influenza circulating in various areas of the country was not determined; therefore, whether geographical differences occurred is not known.
High-dose vaccine adverse events were evaluated based on VAERS (Vaccine Adverse Event Reporting System) reports. A total of 622 reports were received as of February 28, 2011, and most (91.8%) were coded as nonserious. A review of the serious reports showed a slightly higher proportion of gastrointestinal complaint and cardiac conditions (all with preexisting cardiac conditions), but very small numbers of adverse events were observed. CDC and FDA will continue to monitor the adverse event reports.
A total of 158.2 million doses of vaccine were distributed in 2010–11. Overall coverage was 43%, with 66.6% in those older than 65 years. Compared with previous years, a slight decrease occurred in vaccination rates other than in the group aged 18 to 49 years (1% increase). A total of 166 to 173 million doses of influenza vaccine are expected to be available for the 2011–12 influenza season.
During the question-and-answer session, I brought up the discussion concerning the FDA statement disallowing the use of jet injectors for administering inactivated influenza vaccines. I informed ACIP that pharmacies had complied with the order to stop using them. The patients who had received the vaccine do not need the vaccine repeated. I then asked the FDA representative if the agency intended to reconsider this decision, considering that jet injectors are FDA approved. He replied that although the devices are FDA approved, they are not approved for influenza vaccines. A PharmaJet representative made a statement, and the company is continuing to work through this issue with FDA.
The next meeting will be February 22–23, 2012, in Atlanta, GA.
Stephan L. Foster, PharmD, FAPhA
Professor and Vice Chair
College of Pharmacy
University of Tennessee Health Sciences Center
APhA Liaison Representative to the Advisory Committee on Immunization Practices (ACIP)
CAPT (Ret) U.S. Public Health Service