Influenza, herpes zoster, hepatitis A, and more focus of ACIP’s June meeting

Complete minutes available on CDC website

On June 21 and 22, CDC’s Advisory Committee on Immunization Practices (ACIP) met in Atlanta to discuss a variety of immunization topics. A summary of the discussions follows. Complete minutes will be published on CDC’s National Center for Immunization and Respiratory Diseases (NCIRD) website at

Influenza vaccine

ACIP reported that the 2016–17 influenza season was a typical moderate season, but activity peaked a little later than in the previous four seasons. Surveillance data revealed that 70% of the circulating influenza was type A—predominately H3N2—and the remainder were mostly B lineages. The influenza vaccine antigens were a good match for the circulating viruses. The U.S. Flu Vaccine Effectiveness (VE) network showed a VE of 42% overall, with a range of 19% to 61%, depending on age. The VE was 34% for influenza A(H3N2), 54% for A(H1N1), and 56% for type B.

ACIP noted that a new surveillance system, the U.S. Hospitalized Adult Influenza Effectiveness Network (HAIVEN), was developed to look at vaccine protection against more serious cases of influenza. The HAIVEN network consists of 10 hospitals throughout the United States and includes adults older than 19 years. In the 2016–17 season, the overall VE rate in this system was 30% (i.e., 20% H1N1 and 53% B); however, these data have not been analyzed to look at trivalent versus quadrivalent or high-dose versus regular-dose vaccines.

Safety surveillance (e.g., Vaccine Adverse Event Reporting System, Vaccine Safety Datalink, or Medicare Surveillance for Guillain-Barré syndrome) showed no new safety concerns for all vaccine types, but there was no report on the live attenuated influenza vaccine (LAIV). Additional data were presented on the use of Flublok (Protein Sciences) in pregnant women, with no safety signals reported.

In the 2017–18 ACIP Influenza Recommendations (to be published in August 2017), only the A(H1N1) component will change in the vaccine virus composition. New vaccines for use in the 2017–18 season will include Afluria Quadrivalent (Seqirus), Flublok Quadrivalent (Protein Sciences), and FluLaval Quadrivalent ([GlaxoSmithKline] for ages 6 mo and older). As in this past season, the LAIV will not be recommended for 2017–18.

Another change is that Afluria, which was previously recommended for those aged 9 years and older although it was FDA approved for 5 years and older, is now recommended again for ages 5 years and older. The recommendation for use in those aged 9 years and older was based on a higher fever rate seen in 2009. The manufacturing process, as well as the vaccine antigens, have changed since that time, and the fever rate has declined.

In addition, slight changes were made on the wording of vaccination of pregnant women to include all inactivated influenza vaccines (IIV), including recombinant influenza vaccines (RIV).

Herpes zoster vaccine

ACIP reported that a long-term effectiveness study of Zostavax (Merck) using Kaiser Permanente data was conducted from 2007 to 2014 to examine VE based on age and time since vaccination. Average duration of follow-up after vaccination was 2.6 years. Overall VE against herpes zoster (HZ) was 49.1%, which was similar to the Shingles Prevention Study rate of 51%. The VE ranged from 67.5% within 1 year of vaccination to 31% by 7 to 8 years. A small proportion of the patients in this study received Zostavax when they were immunocompromised, and the VE was similar. 

Overall VE against postherpetic neuralgia (HPN) was 68.7%, with a gradual decrease over 5 years.  A GRADE (Grading of Recommendations Assessment, Development, and Evaluation) analysis showed the vaccine was effective in prevention of HZ and HPN; however, the VE decreased over time.

GlaxoSmithKline presented the results of an immunogenicity and safety study on use of its investigational HZ vaccine, Shingrix (HZ/su), in persons who had already been vaccinated with the live HZ vaccine (i.e., Zostavax). The study met the primary endpoint of noninferiority of immunological response to vaccination when comparing use in those with a previous vaccination to those with no previous vaccination. Safety results were similar between the two groups; however, a slightly higher incidence of unsolicited adverse events was noted in the previously vaccinated group. These events were mostly local effects.

The ACIP work group addressed several policy questions now that the efficacy, safety, and cost-effectiveness data of the HZ/su vaccine (i.e., Shingrix) have been reviewed. The questions and the work group’s deliberations follow.

1.      Should ACIP recommend HZ/su for vaccination of immunocompetent adults?

Yes. The number needed to vaccinate (NNV) to prevent one case of HZ over 4 years is 32, assuming two-dose compliance and a slower rate of waning. The NNV over a lifetime is one case prevented for 10 to 13 adults vaccinated.

2.      At what age should HZ/su age-based recommendations start?

Since HZ/su is very effective in the 50- to 59-year-old age group, minimal waning occurs in the first 4 years (after 4 years, it is not known), and approximately 21% of all HZ cases occur in this age group, the work group recommended vaccination beginning at age 50 years. However, the work group is waiting for a final price to compare cost effectiveness.

3.      Should ACIP recommend a preference for HZ/su over Zostavax?

The HZ cases expected for 60-year-olds over a 4-year period is 10 following vaccination with HZ/su and 105 with Zostavax. Unknowns include the two-dose adherence, VE of one dose of HZ/su, and any unexpected safety issues that may arise. A majority of the ACIP members preferred HZ/su, depending on the results of the cost analysis.

4.      Should individuals previously vaccinated with Zostavax receive HZ/su?

Since HZ/su is more effective and a small study showed no safety issues and good immunogenicity following vaccination with Zostavax, the work group said HZ/su should be considered for those who previously received Zostavax.

If Shingrix is FDA approved by October, further discussions will be held at ACIP’s next meeting, scheduled for October 25–26, 2017.

Hepatitis A vaccine

ACIP noted that updates are needed to the revised statement “Prevention of Hepatitis A through Active or Passive Immunization: Recommendation of the Advisory Committee on Immunization Practices,” along with other hepatitis A guidance documents (last published 2006–09).

Cases of hepatitis A have declined by 95% since the 1970s, dropping to a rate of 0.4 cases/100,000 in 2015. Approximately 50% of those infected are hospitalized, and the mean age is 45.5 years. Vaccination of all children has been recommended since 2006, so most of the cases are seen in adults. Two inactivated vaccines and one combination hepatitis A and B inactivated vaccine (Twinrix—GlaxoSmithKline) are available in the United States.

While duration of protection is not known, anti-hepatitis A virus titers have been shown to persist for at least 20 years in adults vaccinated as children, with detectable antibodies estimated to persist for 40 years or longer. Protection is lifelong following natural infection and may also be the same for vaccination. However, two-dose coverage in children is only 59.6% (based on 2015 CDC statistics) and even lower in adults aged 19 to 49 years old (12.1%, based on 2014 CDC statistics). Multiple outbreaks continue in the United States, mostly from contaminated food sources.

The committee presented a cost-effectiveness study to determine whether to implement a catch-up recommendation for the hepatitis A vaccine, the only childhood vaccine without one. Results showed that the incremental cost was $146 million, with an estimated $452,239 per quality-adjusted life-year (QALY) gained. This translated to a reduction of 741 infections, with 556,989 vaccinations administered (or 752 vaccinations to prevent one infection). In addition, cost effectiveness decreased with age. ACIP noted the intervention was not cost effective given the current low disease rate; which would need to increase to 5 cases/100,000 before it would be cost effective. However, this model only considered childhood vaccination and not its effect on herd immunity on adults, nor the effects of childhood vaccination on adult disease, especially as children age into adulthood. While there was no ACIP vote, the work group stated that it prefers a permissive catch-up recommendation to improve population protection, despite the cost-effectiveness calculations. This would increase adult vaccination rates by increasing the childhood cohort.

Other suggested changes included vaccinating high-risk pregnant patients and those with chronic liver disease (changing the definition of liver disease similar to that given in the hepatitis B vaccine recommendation). In addition, ACIP continued discussions on vaccination recommendations in group homes and child care settings and announced that guidelines for postexposure prophylaxis with vaccine alone, immune globulin (IG) alone, or both together are being updated. More data will be presented at future ACIP meetings.

Varicella vaccine

The committee noted that the varicella vaccine has had an impact on varicella disease in children, and the hope is that it will also decrease the incidence of HZ. However, an article published in 2002 predicted that HZ rates in adults would actually increase by decreasing childhood disease and causing a decrease in exogenous boosting by natural disease. Varicella vaccine uptake is approximately 94%, and this has resulted in a decrease of 97% in disease incidence. HZ develops in approximately one-third of individuals over a lifetime, and no factor has been found to distinguish between those who develop disease and those who do not.  

HZ vaccine has not had a major impact on decreasing HZ incidence to date because uptake is low, effectiveness is less than 50%, and titers wane over time. An accelerating trend in HZ has not been seen since the introduction of the varicella vaccine, and a slowing rate has actually been seen in a few studies. What has been demonstrated is a decrease in varicella incidence, outbreaks, and severe disease in all age groups. To date, the incidence of HZ has decreased among children, and varicella vaccination has not accelerated HZ rates in the general population.

Mumps and MMR vaccines

Mumps cases have increased yearly throughout the United States since 2013. These outbreaks had the highest incidence in 18- to 22-year-olds, 73% of whom had been vaccinated with only two doses of the measles, mumps, and rubella (MMR) vaccine. Factors that may contribute to this increasing number of mumps cases include VE (53%–95%), waning immunity, severity of infection, and antigenic differences between the virus and vaccine. 

A few studies performed after three doses of MMR showed that antibody titers develop rapidly following the third dose. Although the titers fell within 1 year, interpretation of these findings is difficult because data on immunological memory are lacking and because there is no known antibody correlate of protection. Epidemiologically, attack rates of mumps decreased after a third-dose campaign, but it was possible that the intervention was after the peak of infection. Another epidemiological study demonstrated that disease risk was related to duration since receiving the second dose of MMR and appeared to be due to waning immunity. No serious adverse effects have been reported with a third dose of MMR.

Meningococcal vaccines

ACIP reported that the immune correlate of protection (serum bactericidal antibody) declines rapidly by 12 months following meningococcal (quadrivalent) conjugate vaccine (MenACWY) vaccination; studies of antibody persistence are ongoing. Eculizumab (Soliris—Alexion) is a complement component inhibitor used in the United States for two rare, life-threatening diseases: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. FDA has issued a boxed warning in the package insert for an increased risk of meningococcal disease. There have been 16 cases of meningococcal disease out of 5,207 person-years of eculizumab exposure (307 per 100,000 person-years reported by the manufacturers). All had received MenACWY vaccines. The serogroups causing infection were serogroup B (1 case), serogroup C (2 cases), and serogroup Y (2 case); 11 serogroups were unknown. 

Both MenACWY and serogroup B meningococcal (MenB) vaccines should be administered to patients receiving eculizumab according to ACIP guidelines. ACIP noted that one patient died from a nongroupable meningococcal strain in spite of elevated MenB-4C (Bexsero—Novartis) antigens collected in the patient’s blood at the time of death. Nongroupable strains rarely cause infections. A review of other cases demonstrated 50% of cases of infection were caused by nongroupable strains. Vaccination appears to cause incomplete or no protection for patients receiving eculizumab, suggesting that antibody prophylaxis may be necessary in patients receiving this drug.


Humans are the primary host of dengue, which is transmitted by the mosquito. Although four dengue serotypes provide long-term protection following infection, there is no cross protection between them, which means that an individual can be infected four times in a lifetime. Dengue causes an acute febrile illness that can be severe. It is endemic in the Caribbean and Pacific Island regions and highly endemic in Puerto Rico, with simultaneous circulation of multiple serotypes. Nonendemic outbreaks have occurred in Texas, Florida, and Hawaii.

Yellow fever vaccine

The shortage of YF-Vax (Sanofi) vaccine has been caused by transitioning of production to a new facility and shutdown of the old facility. During this shortage, the Stamaril (Sanofi) vaccine is being imported from France and distributed under FDA guidance. The Expanded Access Program is allowing 250 sites to distribute the vaccine under an investigational new drug (IND) protocol. The sites, which were selected on the basis of volume of yellow fever vaccine distributed the previous year, must sign an agreement, undergo training, follow a protocol, track vaccine use, and monitor safety. The new manufacturing facility will start supplying YF-Vax by mid-2018. 

For the IND, patients will be required to be screened for inclusion and exclusion criteria, sign a consent, and report any adverse effects that occur. The exclusion criteria are stricter than current ACIP recommendations and include women who are breastfeeding, as well as infants aged 6 to 8 months.