The Advisory Committee on Immunization Practice (ACIP) met in Atlanta, GA, on June 22–23, 2011. Complete minutes of the meeting will be published on the CDC National Center for Immunization and Respiratory Diseases (NCIRD) website.
The herpes zoster vaccine Zostavax (Merck) was recently approved by FDA for use in patients aged 50 to 59 years. It has been in use since 2006 in patients older than 60 years. The FDA approval was based on the Zostavax Efficacy and Safety Trial (ZEST).
Merck presented the supply issues that have been a problem since 2007. The supply of varicella vaccine (Varivax) has not been affected. This live virus vaccine is difficult to produce and takes approximately 1 year to manufacture one batch. The biggest problem has been variability in bulk vaccine yields. Merck plans to produce about 2 million doses for the rest of 2011 and exceed this number in 2012. Also, substantial funds are being invested in new facilities for vaccine production.
The clinical presentation and complications of herpes zoster disease were presented. The data showed a worsening of disease symptoms and complications, including hospitalizations and death, as age of the patient increases. A review of the original zoster study (Shingles Prevention Study), which was the basis for Zostavax approval, was presented.1 A recent study by Tseng et al.2 was performed in a large Kaiser Permanente Population and demonstrated a vaccine effectiveness of 55%, similar to the Shingles Prevention Study. As mentioned in the February report, ZEST was the basis for the March 2011 FDA approval for patients 50 to 59 years age. The trial showed a vaccine effectiveness of 69.8% and a small increase in the local and systemic reactions compared with placebo but did not show an increase in serious adverse effects. The mean follow-up was 1.3 years. ZEST demonstrated a decrease in vaccine efficacy with age.
The duration of protection of zoster vaccine is unknown. The studies have shown that the vaccine protects for at least 3 to 4 years and may last longer. A long-term persistence study is currently under way. Whether the vaccine will protect 15 to 20 years if given at age 50 years is not known. To be accurate, cost-effectiveness calculations must include duration of protection, which is a factor that is currently unknown. Calculations with the assumptions that the vaccine duration of protection lasts either 10 years or a lifetime result in vaccination at age 70 years being the most cost effective.
Last, adding patients aged 50 to 59 years would require a great increase in the number of individuals needing vaccine. This would dilute the amount of vaccine available for those in the highest risk of zoster disease. ACIP has never recommended an expansion of a vaccination program during a supply shortage.
In conclusion, the zoster working group does not propose an expansion of existing recommendations regarding zoster vaccine at this time.
Varicella: Impact of two-dose program
ACIP recommended a change from a one- to two-dose varicella program in 2006. The recommendation was based on multiple outbreaks in highly vaccinated schools showing incomplete protection following one dose. With the exception of three states, very high two-dose coverage is occurring in the United States (85–100%). The states with lower coverage generally do not have kindergarten vaccination requirements. These rates are even lower among adolescents. Safety surveillance reports have demonstrated that the vaccine is safe, with rare local reactions reported following the second dose. The Varicella Active Surveillance Project, which follows disease in several sites around the country, has demonstrated a decline in varicella incidence since 2006. The majority of cases of varicella in vaccinated cases are those who have only received one dose; however, two-dose cases have been reported. In addition, the number of outbreaks in one site has decreased by one-half (from 46 in 2002–05 to 21 in 2006–10). This two-dose program has been highly effective.
The meningococcal vaccine working group has been focusing on updating the 2005 ACIP recommendations. An update in January 2011 recommended a booster dose for meningococcal conjugate vaccine (Menactra—sanof pasteur). In April, Menactra was approved by FDA for children 9 to 23 months of age with a booster 3 months later. Within the next year, two more vaccines for infants are expected to be approved by FDA for use at 2, 4, 6, and 12–15 months.
Sanofi pasteur presented the safety and efficacy data for Menactra’s new indication. In the United States, strains C (29%), Y (33%), and B (29%) are responsible for the majority of disease. Type B antigen is not contained in the available U.S. vaccines. Immunogenicity, based on serological assays, showed consistently high titers following two doses in children aged 9 to 23 months, although duration of protection is less than 3 years. Also, the antibody response was considered protective when coadministered with the measles–mumps–rubella–varicella vaccine and 7-valent pneumococcal conjugate vaccine (PCV7), although the pneumococcal serotype titers were lower with the combination. Local and systemic reactions were not increased when Menactra was given with other vaccines. Of note, no data are available regarding the combination of Menactra and 13-valent pneumococcal conjugate vaccine (PCV13).
The working group identified infants at high risk for meningococcal infection. These included infants with complement deficiencies, those with asplenia, those exposed during outbreaks, and those traveling to endemic areas. These groups would include about 5,000 U.S. infants.
ACIP recommended administering the vaccine to infants at high risk for disease at 9 through 23 months of age, as well as a booster 3 months later, with the exception of children with functional or anatomic asplenia. The working group will reconsider this group after more data on the lowering of pneumococcal titers are available.
A new meningococcal type A vaccine (MenAfriVac) has been added to an already large mass vaccination campaign targeting Africans aged 2 to 29 years. A significant decrease in disease has occurred since the campaign began in the mid-2000s. Within 10 years, the hope is to eliminate the meningitis belt in sub-Saharan Africa.
A total of 156 cases of measles have been reported in the United States in 2011. Of these cases, 85% involved unvaccinated patients or patients with an unknown vaccination status. About one-third (34%) have been hospitalized. A high percentage of the cases (87%) were associated with importation of disease from abroad, with the majority originating in Europe—large outbreaks have occurred in France, Spain, and Belgium. A total of 12 outbreaks have occurred in the United States, each with 3 to 21 cases per outbreak.
Although tetanus–diphtheria–acellular pertussis (Tdap) vaccine recommendations were broadly expanded at previous ACIP meetings, vaccination during pregnancy was postponed. Current recommendations are to give tetanus–diphtheria (Td) vaccine if needed during pregnancy (though Tdap may be used), Tdap as soon as feasible postpartum, and cocooning with Tdap administered to family members who will have contact with the infant.
Typically, inactivated vaccines are considered safe during pregnancy while live vaccines are contraindicated. Certain vaccines are considered indicated in pregnancy, including influenza and tetanus toxoid, which have had no evidence of increased risk to mothers or pregnant women.
Data from the Vaccine Adverse Event Reporting System (VAERS) following Tdap in pregnancy have shown no unexpected patterns of events. Similar results were seen in reports from Phase IV trials by sanof pasteur. In conclusion, current data suggest that potential risks (if any) are likely to be minor.
Cost effectiveness of Tdap vaccination compared with cocooning was presented. A total of 18 variables, or assumptions, were used in the calculations. The cost per quality-adjust life year was lowest when the vaccine was given during pregnancy compared with the various cocooning methods.
Currently, a double-blind, randomized, controlled clinical trial is under way in Canada comparing Td with Tdap in pregnant women. It is expected to be completed by December 2012. Initial analysis of blinded results showed that a difference in antibody levels occurred in infants at 0, 2, 4, and 6 months of age between the two groups; however, the results remain blinded.
An evaluation of cocooning demonstrated that this method of infant protection was minimally effective, primarily because of poor rates of fathers and other family members getting vaccinations and poor uptake of vaccination at birthing hospitals. The working group suggested that cocooning is a poor national strategy to prevent mortality or morbidity in infants. Most experts consider Tdap safe during pregnancy, programmatic costs are equal because vaccination is recommended postpartum, and Tdap will protect the pregnant women and infant.
ACIP voted to recommend Tdap vaccination in pregnancy, preferably during the late second or third trimester (after 20 weeks) if patients have not received a previous dose of Tdap vaccine. If not administered during pregnancy, Tdap vaccine should be administered immediately postpartum. Cocooning of family members is still encouraged.
Human papillomavirus vaccine
Data related to vaccination of men were reexamined because of new information available regarding anal and oropharyngeal cancer. Quadrivalent human papillomavirus vaccine (HPV) vaccine was approved for use in men and was given a permissive recommendation by ACIP in 2009. To date, reports have shown no waning of protection for more than 5 years postvaccination; however, studies are ongoing.
Merck presented data from two long-term studies for duration of protection, one of which was a follow-up study to the original Phase III studies. These results are 6 years out from the original studies in Nordic countries that maintain cancer registries. The vaccine effectiveness for cervical intraepithelial neoplasia (CIN) grade 2 or higher caused by HPV type 16 or 18 in the per-protocol analysis continues to be 100% (0 of 1,080). Because of low numbers in this group, these results have not reached statistical significance. Of 1,217 patients, 3 cases of CIN lesions due to nonvaccine HPV types have been observed. The investigators concluded that Gardasil continues to be protective for up to 7 years and is generally safe and well tolerated. Another study looked at serology titers compared at months 7 and 72. Titers were similar for types 6, 11, and 16; titers were lower with type 18. Clinically, no cases of type 18 were seen in spite of lower titers.
Oropharyngeal cancers are primarily a result of HPV type 16 and are increasing in incidence. Also, the percent of oropharyngeal cancers caused by HPV are increasing from about 30% in 1984–89 to 75% in 2000–04. Looking at various studies, risk factors for oral HPV infection include age, gender, sexual behavior, current tobacco use, and HIV infection. Direct evidence of vaccination protection against oral HPV infection is lacking. Cost-effectiveness data show that if female coverage was high, then male vaccination is not cost effective; however, at current levels of female coverage, male vaccination is potentially cost effective.
At the October ACIP meeting, policy consideration will be given to changing the recommendations for men. Also, a stronger recommendation for vaccination among men who have sex with men will be considered. If a routine recommendation option is approved for male patients, the catch-up issues will need to be discussed. An additional consideration will be given to restricting catch up in both male and female patients to age 21 years.
Vaccines and febrile seizures
A subgroup of the General Recommendations Committee was created to look at the incidence of febrile seizures with vaccines. This was requested because of reports of an increase in febrile seizures with influenza vaccine and PCV13.
In general, febrile seizures occur in about 2% to 5% of children aged 6 to 60 months. Simple febrile seizures (97%) last less than 15 minutes with no recurrence. Complex febrile seizures are focal, last longer than 15 minutes, and may reoccur within 24 hours. Children with febrile seizures have the same risk of developing epilepsy as the general population. The two biggest problems with febrile seizures are the stress to the family and cost of medical evaluation.
Following a review of VAERS data and the Vaccine Safety Datalink project, no increase in febrile seizures was seen with influenza vaccine used alone. However, a slight increase was seen in the 2010–11 season with the concomitant administration of trivalent inactivated influenza virus (TIV) vaccine and PCV13. This risk was seen in 12- to 23-month-old children who received the first dose of TIV plus PCV13. Risk was 61 per 100,000, or 1 febrile seizure in 1,640 vaccinees.
Updated data have been received based on a chart review of confirmed febrile seizures with TIV plus PPV13, and the results are actually lower (1 febrile seizure in 2,375 vaccinees).
The risks of complications from influenza in the group aged 12 to 23 months were presented as follows: hospitalizations 3 to 11 per 10,000, 0.77 deaths per 100,000, and extremely high costs for hospitalizations and emergency department visits. Also, influenza disease was responsible for 10% to 20% of hospitalized febrile seizures in various studies. Another study showed that influenza was responsible for a rate of hospitalizations of 9 per 10,000 among the group aged 12 to 23 months and that seizures were reported in 8% of these patients. Similar findings have been reported for pneumococcal disease: 42,000 hospitalizations in children younger than 5 years and 1 million episodes of illness. PCV7 has been associated with the prevention of 211,000 cases of invasive pneumococcal disease.
The workgroup concluded that the risk of disease was much greater than the risk of febrile seizures. A concern is that if too much emphasis is placed on potential adverse events, parents will not vaccinate. Educating parents about febrile seizures is important and should probably begin at birth. No change was made to the ACIP recommendation.
Again, diabetes and hepatitis were discussed. Among adults aged 20 to 59 years, the incidence of hepatitis B was significantly higher among those with diabetes compared with those without diabetes. For patients older than 60 years with and without diabetes, the incidence of hepatitis B was not significantly different.
In the group aged 20 to 59 years, an estimated 5,071 infections would be prevented and 304 chronic cases prevented. The cost effectiveness increases as age increases because the incidence of hepatitis B decreases with age along with declining vaccine efficacy.
The working group is proposing hepatitis vaccination for unvaccinated adults with diabetes younger than 60 years of age and using individual clinical decisions for those older. More data will be available at the October meeting, and a vote is expected.
Conjugate pneumococcal vaccine in adults
A new indication for PCV13 (Prevnar—Pfizer) in adults 50 years or older is expected for later this year. Pfizer presented nonclinical models to estimate vaccine effectiveness. Some of the assumptions were based on a study of PCV13 in adult patients with HIV. Clinical data in the group older than 50 years are not available at this time.
Invasive pneumococcal disease (IPD) has significantly decreased in adults since the introduction of PCV7. Serotypes contained in the 23-valent pneumococcal polysaccharide (PPSV23) vaccine and not contained in PCV13 account for 20% to 30% of IPD in adults.
Trials comparing PVC7 and PPPSV23 have shown better titers against select serogroups with PCV7, but not to all serotypes. These trials are difficult to compare because of the large number of serotypes responsible for disease. Additional trials are ongoing to prove or disprove some of the assumptions used in the calculations of effectiveness.
A review of egg allergy and influenza immunization was performed by a group developed by CDC: the Clinical Immunization Safety Assessment Network Hypersensitivity Working Group. Patients who have immunoglobulin E–mediated egg allergy have a risk for anaphylaxis; however, the risk for withholding influenza vaccination is far greater. A total 17 published studies involving more than 2,600 confirmed egg-allergic patients have shown no serious reactions to vaccination and low incidence of minor reactions (e.g., hives, mild wheezing). Also, skin testing is not predictive of a reaction. The level of ovalbumin in the vaccine does not appear to be high enough to cause a problem. This working group concluded that influenza vaccination is not contraindicated in a patient with egg allergy but that caution should be taken. If patients report egg allergy, the allergist giving the report suggested referring them to an allergist for testing because the allergy is often outgrown. Also, skin testing for vaccination or splitting the dose of vaccine is not recommended. However, the vaccine should be administered in a location where anaphylaxis can be treated and patients should remain under observation for 30 minutes. This approach was published in a joint statement of the American Academy of Allergy Asthma & Immunology, the American College of Allergy Asthma & Immunology, and the Joint Council of Allergy, Asthma and Immunology.3 Also in agreement is the National Institute of Allergy and Infectious Diseases, with the exception of suggesting use of a vaccine with a low amount of ovalbumin (<0.1 mcg/ml). ACIP proposed and voted that patients with mild allergy (hives only) should receive TIV (not live attenuated influenza vaccine), should receive a low ovalbumin product (<0.6 mcg/ml), and should be observed for 30 minutes. Patients with a higher risk for severe reaction should be referred for further risk assessment before receiving the vaccine.
Influenza activity in the United States is showing a mixture of H1N1, H3N2, and type B. Since October 1, 2010, 2,494 viruses reported to CDC have been categorized as follows: 24% H1N1, 46% H3N2, and 30% type B. The viruses continue to be susceptible to neuraminidase antivirals and resistant to adamantine antivirals. The highest number of cases was reported in February 2011. A total of 110 pediatric deaths were reported for the 2010–11 flu season. Activity remains low at this time, and all three strains continue to circulate.
Influenza facts (2010–11 season):
The next meeting will be October 25–26, 2011, 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