CDC’s ACIP discusses vaccines for influenza, HPV, and more

The next ACIP meeting is scheduled for October 24–25, 2018

CDC’s Advisory Committee on Immunization Practices (ACIP) met in Atlanta on June 20–21 to review a variety of immunization topics, including influenza, HPV, and more. ACIP’s recommendations aren’t official until accepted by CDC and published in CDC’s Morbidity and Mortality Weekly Report.

Complete meeting minutes will be published on CDC’s website at www.cdc.gov/vaccines/acip/meetings/meetings-info.html. The next ACIP meeting is scheduled for October 24–25, 2018.

Influenza

ACIP voted to approve updating the 2018–19 recommendations to state that LAIV (live attenuated influenza vaccine) language is now an option, and that Fluarix Quadrivalent (GlaxoSmithKline) is now licensed for children older than 6 months, along with FluLaval (GlaxoSmithKline) and Fluzone (Sanofi Pasteur). The updated recommendations were proposed by the ACIP working group.

The 2017–18 influenza season was ranked as a high-severity season for all age groups. According to preliminary end-of-season vaccine effectiveness data, A(H3N2) was the primary serotype circulating (58% of all samples tested), followed by B(Yamagata) at 30%, and A(H1N1) at 10%. The adjusted vaccine effectiveness was 40% against all influenza strains, 24% for A(H3N2), 65% for A(H1N1), and 49% for serotype B(Yamagata). The U.S. Hospitalization Influenza Vaccine Effectiveness Network (HAIVEN) also reported the adjusted vaccine effectiveness against influenza. Their data showed it to be 22% against all influenza strains, 16% for A(H3N2), 58% for A(H1N1), and 35% for serogroup B(Yamagata).

Although the season had high severity, vaccination reduced a significant number of outpatient visits and hospitalizations. ACIP noted more efforts will be expended to determine factors that could be used to engineer more optimal vaccine viruses.

Vaccine effectiveness was previously reported to differ between egg-cultured vaccines and cell-cultured vaccines. A large observational study was performed in patients older than 65 years to assess hospitalizations and office visits from August 2017 to April 2018—over only one influenza season.  The cell-based vaccines and high-dose vaccines performed slightly better than traditional egg-based vaccines in reducing hospitalizations and office visits for influenza among patients older than 65 years. These data are limited because they looked at only one season, so effects across multiple seasons are currently unknown.

ACIP also reviewed the safety of influenza vaccines. The Vaccine Adverse Event Reporting System (VAERS) safety surveillances over this past season showed no new safety concerns for all influenza vaccines. Next year, CDC will monitor the safety of Fluad (Seqirus) and Flublok (Protein Sciences), assess pregnancy reports, and monitor anaphylaxis in patients with an egg allergy.

Seqirus reported a study that compared Fluad—its adjuvanted quadrivalent influenza vaccine—with nonadjuvanted influenza vaccine in children aged 6–72 months. No increased benefit with Fluad was shown in children aged 6–72 months; however, efficacy was greater in those aged 6–24 months. The safety evaluation demonstrated an increase in local and systemic reactions, including fever, with Fluad compared with the regular influenza vaccine. This vaccine is not yet approved by FDA for this age group. 

SOMNIA was a case-report study performed to determine the significance of reports of narcolepsy caused by the ASO3-adjuvanted pandemic H1N1 vaccine (Pandemrix). Pooled data from multiple countries were used. The rate of narcolepsy observed did not increase.

HPV

Merck submitted an application to FDA for expansion of 9-valent human papilloma virus (9vHPV) (Gardasil) vaccine for males and females aged 45 years and younger. Currently, only the 9vHPV vaccine is available in the United States, and it is approved for females and males aged 9–26 years. A 4vHPV vaccine efficacy trial was submitted to FDA in 2008 but was not approved because of a lack of statistically significant efficacy for prevention of cancer associated with CIN (cervical intraepithelial neoplasia) grade 2 or worse. HPV vaccines have been approved in older patients in other countries. Recent efficacy trials have shown per-protocol efficacy of 83%–84%; however, the sample sizes have been small. 

An efficacy trial using the 4vHPV vaccine was conducted in females aged 24–45 years that showed statistically significant efficacy against persistent infection, CIN, and external genital lesions caused by vaccine types. No 9vHPV vaccine efficacy trial has been conducted in males or females older than 26 years, nor have 4vHPV vaccine efficacy trials been conducted among males in this age group. Bridging efficacy and immunogenicity data that were accepted for other HPV vaccine approvals will be used for consideration of the expanded age application.

Merck presented a 10-year study of use of the 4vHPV vaccine in patients aged 24–45 years as a follow-up to the original studies presented to FDA. It was noted that no cases of HPV4 type disease have occurred over the 10 years. Bridging studies of immunogenicity were examined. The geometric mean titer (GMT) results showed that those aged 27–45 years were noninferior to females aged 16–26 years for all four HPV types and to males for three of the four HPV types; type 18 had a lower confidence interval of 0.61, below the FDA lower limit set at 0.67. Postmarketing studies of the 9vHPV vaccine continue, as required by the European Medicines Agency. Unknowns still exist about HPV incidence and disease factors and about immunity following natural infection and its effect on vaccination. Thus, updated modeling and cost-effectiveness studies will be used for discussion of policy considerations.

Pneumococcal

ACIP must decide if the use of PCV13 in adults aged 65 years and older should be continued. While efficacy of PCV13 against invasive pneumococcal disease (IPD) and pneumonia was proven in the CAPITA trial, the vaccine’s effectiveness when used alone or with PPSV23 is not known. By definition, efficacy is demonstrated in small clinical trials, while effectiveness is demonstrated in large population trials. The current evidence presented to ACIP to date included the following:

  1. Pneumococcal carriage among adults ≥ 65 years is very low (8%).
  2. Carriage in children declined from 8% in 2011 to <1% in 2017.
  3. PCV13 coverage among adults ≥ 65 years is approximately 40%.
  4. Vaccine-type IPD (invasive pneumococcal disease) has declined in all age groups (68% in adults ≥ 65 years) and plateaued in 2014–16.
  5. Recent studies showed PCV13 effectiveness against IPD to be 47%–65% and against pneumonia to be 73%.

CDC reported on the safety of PCV13 in adults older than 65 years. The most common adverse effects, as expected, have been injection site pain and mild systemic reactions. A review of the VAERS reports showed that, in addition to the expected common adverse effects, there were 39 cases of Guillain-Barré syndrome, four cases of anaphylaxis, and 26 reports of death, with cardiac causes being the most common.  These were felt to be not vaccine-related. Most of the serious adverse effects were thought to be related to concurrent medical conditions, with no safety signals or patterns observed.

A further analysis of the Pfizer-sponsored study, performed in St. Louis, showed a higher incidence of community-acquired pneumonia (CAP), with an incidence of 2,327 per 100,000 cases of hospitalized CAP in unvaccinated adults. Higher than recognized in two other studies, this is thought to be caused by inclusion criteria of hospitalized and immunosuppressed patients. Previous studies included outpatient individuals who were not immunocompromised. Another analysis of this study showed a decrease in vaccine-type community-acquired pneumonia (VT-CAP) in adults aged 65 years and older but not in adults aged 18–64 years. It was suggested that this proves it is a direct effect of vaccination in older adults and not an indirect effect caused by pediatric vaccination.

Another study of American Indians showed PCV13-type carriage was low before the introduction of vaccination and remains low. The indirect effect of vaccination on IPD substantially reduced disease in those older than 65 years. Vaccination in adults had little additional impact. Most of the CAP occurred from non-PCV13 serotypes during the time period between March 2016 and 2018.

Another analysis of IPD incidence by race found that IPD has decreased for all racial groups and that disparities in IPD between black and white races still are caused by non–vaccine-type IPD. More studies are being performed to determine if these disparities are caused by socioeconomic status or prevalence of certain chronic medical conditions.

Future presentations will include continued updates about PCV13 impact on all-cause pneumonia, cost-effectiveness of changing the PCV13 policy, and public health impact.

Mumps

During a mumps outbreak, ACIP recommended the addition of a third dose in those fully immunized, and left the decision of when this should occur up to public health authorities. A guidance document developed to help make this decision included the number of persons at risk who may be exposed through close contact with a mumps patient and the risks for transmission based on intensity and frequency of exposure. A decision matrix was developed; if “increased risk,” vaccination should be recommended. Other guidance factors must be included in the decision.

Mumps outbreaks have continued over the last few years, although a decrease in the number of cases appears to be occurring. CDC will continue to monitor mumps outbreaks.

Herpes zoster

Through postmarketing surveillance, recombinant zoster vaccine (RZV) (Shingrix—GlaxoSmithKline) continues to be assessed for safety, reactogenicity, and immunogenicity. Most reports to VAERS at this time have been on injection-site pain and redness, fever, and headaches. Also, administration errors are increasing, and CDC has developed fact sheets for providers. CDC is exploring opportunities to study RZV safety; effectiveness; implementation, particularly of two-dose completion; and supply issues.

Japanese encephalitis

Japanese encephalitis (JE) is the leading cause of encephalitis in Asia. There is no antiviral therapy, only supportive care. The risk for JE for most travelers is very low, with an incidence in the United States of approximately one case per year. The only vaccine available in the United States is Ixiaro (Valena) at a cost of approximately $600 for the two-dose series. FDA approved it for use in persons aged 2 months and older. There are no efficacy data for JE vaccine; however, there is an immunologic correlation of protection. A GRADE (Grading of Recommendations Assessment, Development, and Evaluation) analysis was presented on newly available safety and immunogenicity data. This information will be further analyzed and evaluated.

From 1992–2017, only 12 JE cases were seen among U.S. travelers. This low number is not related to vaccination. Only 11%–28% of higher-risk cases were vaccinated, and only 2%–4% of low-risk travelers were vaccinated.

ACIP recommended the JE vaccine for travelers who plan to spend a month or longer in endemic areas during JE virus transmission season, and consideration for shorter-term travelers to endemic areas if their itinerary will increase the risk of JE virus exposure. JE vaccine is not recommended for short-term travelers whose visit is restricted to urban areas or times outside of transmission season.

The vaccination is cost-effective for local populations in endemic countries; however, the vaccine costs less in those countries. For U.S. travelers, the number needed to treat to prevent one JE outcome in high-risk groups is 735,994 at a cost of $596 million. Looking at the lower-risk group of those who spend more than 20% of their time in outdoor, rural areas, the cost is even higher. These results will be used as part of the “Evidence to Recommendations” assessment to be performed by the ACIP workgroup.

Anthrax

The Anthrax Vaccine Adsorbed (AVA) (Biothrax—Emergent Biosolutions) is licensed for both I.M. (i.e., pre-exposure prophylaxis) and S.C. (i.e., postexposure prophylaxis). When the demand for AVA exceeds supply, as in a mass exposure, S.C. administration would be dose-sparing.  Since anthrax cases are rare, and studies in humans would be highly toxic, a correlate of protection in animals to determine proper doses and safety was used to conduct a GRADE analysis. 

The dosing schedule has changed for pre- and postexposure prophylaxis using AVA. There are, however, little data on use in special populations, including pediatrics. No safety issues have been reported, and safety studies support the use of AVA given the high mortality associated with anthrax.

Concerns were expressed that the use of S.C. administration may present problems in a mass vaccination situation, even though better levels were achieved with S.C. delivery. The ACIP working group felt that the S.C. route is preferred, but I.M. could be used if S.C. is challenging. Concerns also exist about dose-sparing regimens if supply becomes an issue. The working group felt that dose-sparing schedules of vaccines could be used, and 42 days of antimicrobial prophylaxis would be sufficient.

ACIP voted to support the I.M. route if necessary, that dose-sparing schedules may be used, and that antibiotics can be discontinued after 42 days for those aged 18 years and older and after 60 days in pediatrics.

National Immunization Technical Advisory Groups

CDC and the World Health Organization have partnered with multiple groups around the world to provide technical assistance in the areas of training materials, tools, and facilitation. The ultimate goal is to support national and worldwide immunization goals with scarce resources.