ACIP meeting focused on influenza, HPV, and much more

ACIP’s next meeting is scheduled for February 27–28, 2019

CDC’s Advisory Committee on Immunization Practices (ACIP) met in Atlanta on October 24–25, 2018, to discuss new FDA label updates for select influenza vaccines, expanded use of the human papilloma virus (HPV) vaccine in adults up to 45 years of age, and a variety of other immunization topics. The following is a summary of the discussions; complete minutes of the meeting will be published on CDC’s website at www.cdc.gov/vaccines/acip/. ACIP’s next meeting is scheduled for February 27–28, 2019.

Influenza
FDA has made several labeling changes to various influenza vaccines. Afluria Trivalent and Quadrivalent (Seqirus) received an age expansion for use as young as 6 months. The following five influenza vaccines are now approved for patients aged 6 months to 35 months; however, the doses are different for each. 

Fluarix Quadrivalent (GlaxoSmithKline)        0.5 mL
FluLaval Quadrivalent (GlaxoSmithKline)        0.5 mL
Fluzone Quadrivalent (Sanofi Pasteur)        0.25 mL
Afluria Trivalent (Seqirus)                0.25 mL
Afluria Quadrivalent (Seqirus)            0.25 mL
For individuals aged 3 years and older, the doses for all these vaccines is 0.5 mL.

The workgroup noted that while influenza vaccination has been studied in the prevention of mild- to moderate-severity influenza, minimal data exist on the prevention of severe outcomes. A worldwide cooperative study looked at influenza hospitalizations and showed influenza vaccination had the potential to prevent 40% of influenza hospitalizations during pregnancy.

Monica Mercer, MD, director of scientific and medical affairs at Sanofi Pasteur, presented data on the use of full-dose (0.5 mL) Fluzone in children aged 6 months to 35 months. Current recommendations are to use 0.25 mL (one-half dose) in this age group. The study looked at both one- and two-dose series and demonstrated that full-dose Fluzone Quadrivalent had a safety profile similar to that of half-dose Fluzone Quadrivalent. Immunologic markers (geometric mean titre and seroconversion rates) met noninferiority criteria for all four strains for full-dose vaccine compared with half-dose vaccine. A biologics license application (BLA) has been submitted to FDA for use of this increased dose in children.

HPV 
The workgroup reported on a CDC study published in Pediatrics on primary ovarian insufficiency (POI), a condition of premature menopause and ovarian failure, and adolescent vaccination. The estimated prevalence of natural occurring POI is 1 per 10,000 females, most cases are idiopathic, and POI may be associated with autoimmune or infectious diseases. In a search of the Kaiser Permanente Vaccine Safety Datalink for POI in 200,000 patients from August 1, 2006, through December 31, 2014, CDC found a prevalence of 231 cases per 10,000 females. Only 28 cases could be confirmed, and only one person had exposure to the 4-valent HPV vaccine before onset of symptoms. The authors concluded an increased risk of POI was not observed in this study.

On October 6, 2018, FDA approved an expanded indication for use of the HPV vaccine through age 45. Since the end of 2016, only the 9-valent HPV vaccine (Gardasil 9—Merck) has been available in the United States. While this vaccine just received FDA licensure in the United States for an expanded age (26–45 y), it has been used in this age group in other countries for several years. The licensure expansion was based on additional follow-up of patients enrolled in previous studies of the 4-valent HPV and observational studies lasting up to 10 years. No data are available for 9-valent HPV vac-cine in this age group; however, studies are ongoing.

HPV vaccination coverage among adolescents ranges from 55% to 70% for one dose and 40% to 50% for series completion. Data collected by CDC show that the 4-valent HPV vaccination is having an impact in decreasing disease prevalence of the four vaccine types up to age 30. While expanding the age indication to age 45 has potential benefits, there are many unknowns. Fifty percent of HPV exposures occur by age 21 years, and 75% occur by age 31 years. Not all these exposed persons develop antibody following infection, and the percentage of persons who are able to clear the infection is not known. 
The impact of vaccination may be influenced by the likelihood of previously having an infection of an HPV type in the vaccine; the immunity developed following infection; the risk of infection by another HPV type; or the vaccine efficacy against reinfection with a previously cleared infection. Most newly acquired infections in women aged 25 to 65 years are attributed to having new partners. A review of vaccine effectiveness studies found lower vaccine effectiveness with in-creasing age. This supports the importance of vaccination in early adolescents. The data presented to FDA to support ex-tending the age indication found the vaccine efficacy high in women naive to the types found in the vaccine but lower in the general population.

A Grading of Recommendations Assessment, Development, and Evaluation (GRADE) analysis demonstrated that the 9-valent HPV is more efficacious against HPV-related outcomes than no vaccination. Three preliminary health economic models were presented relating to catch-up vaccination up to age 45 years. Current vaccination recommendations are cost-saving, and increasing the age results in a substantially higher cost per quality-adjusted life-year (QALY) gained. Most of the workgroup members agreed that an “individual decision making” recommendation through age 45 years should be considered; however, guidance would need to be provided. More economic analysis will be presented at the February 2019 ACIP meeting, with a potential vote at that time.

Pneumococcal
When ACIP made the recommendation to add the pneumococcal conjugate vaccine, 13-valent (PCV13), for adults aged 65 years and older, a re-evaluation was suggested by ACIP. This re-evaluation was to see if vaccination would be unnecessary after 2018 because of herd immunity resulting from pediatric vaccination.  

The overall incidence of invasive pneumococcal disease (IPD) is significantly lower since the introduction of PCV13 in children in 2010. This reduction is primarily driven by decreases in serotypes 19A, 7F, and 6C (cross-protection). There has been little change in serotype 3 reduction since 2007. Overall rates of IPD have plateaued since 2014, and the direct effects of PCV13 on IPD in adults appear to be small. There also has been no serotype replacement following this reduction. Adding serotypes not currently in PCV13 would not make a significant impact on disease incidence. 

An example of this was mathematically calculated and showed that adding the most common seven serotypes not contained in vaccines to the PCV13 vaccine would only result in a reduction of approximately 700 IPD cases per year in the United States. The PCV13 vaccine for children continues to reduce disease in adults through herd effects. Another model demonstrated that pneumococcal pneumonia in adults continues to contribute to a high burden of disease among adults. Most of the decreases in adult cases were seen before 2014, with very little additional reductions seen after that year.

 
CDC analyzed the impact of changing to PCV13 on pneumonia and IPD prior to the adult vaccination recommendation. Statewide hospitalization data from 2005 to 2014 were analyzed. All-cause pneumonia in children aged newborn to 4 years declined, but no declines occurred in children aged 5 years to 17 years or in adults. Pneumococcal pneumonia hospi-talizations declined in all age groups, but no declines occurred in IPD hospitalizations for those aged 40 to 64 years or 75 or older. CDC concluded that all-cause pneumonia in persons older than 5 years did not decrease likely because PCV7 had already been used since 2000, and most disease was caused by nonvaccine serotypes. Direct and indirect effects were observed for pneumococcal pneumonia and IPD after switching to PCV13 in 2010, with no decline in IPD hospitalizations in older adults.

An economic analysis on continuing or discontinuing PCV13 in adults was presented. This analysis did not evaluate changing the pneumococcal polysaccharide vaccine, 23-valent (PPSV23) recommendations. The analysis suggested that a cost per QALY range for PCV13 in adults ranged from $567,511 to $648,845, which is much higher than the projection made in 2014 ($286,855). 

Using the data collected thus far, ACIP applied a partial preliminary Evidence to Recommendation (EtR) Framework. This new objective method of evaluation adopted by ACIP is a systematical review that includes background, evidence, criteria, and balance of consequences, which leads to guidance for an ACIP recommendation. No ACIP vote was taken on this topic, as the results of additional pneumonia studies will be presented at the next ACIP meeting, with a potential vote occurring at that time.

To summarize, all-cause pneumonia is a significant cause of disease in adults aged 65 years and older, but only about 5% of cases are caused by the PCV13 serotypes. Most of the decline was seen before the 2014 recommendation.

Pertussis
The current recommendation for pertussis vaccination is a single dose of Tdap at age 11 to 12 years, a single dose for those older than 11 years if not previously vaccinated, and one dose with every pregnancy. Booster doses every 10 years are to be administered with Td. Since many providers do not stock both Td and Tdap, they would like to booster with Tdap and stock only one.  

Sanofi Pasteur has filed a new BLA with FDA to allow booster doses of Adacel (Tdap) to be given. No safety concerns have been seen in the booster studies. Postvaccination seroprotection rates of diphtheria in Adacel were noninferior compared with those of Td; however, noninferiority for tetanus was not achieved. However, seroprotective antibody concentrations for tetanus were high following a booster dose. Two of the four pertussis antigens met noninferior criteria, and two did not. Sanofi Pasteur said it did not think these results would impact the effectiveness overall. In addition, GlaxoSmithKline presented Boostrix booster studies, in which noninferior criteria were met. ACIP will await a response from FDA before making recommendations.

Hepatitis A
A new ACIP recommendation, use of hepatitis A vaccine for postexposure prophylaxis and for pre-exposure prophylaxis for international travel, was published in the MMWR in early November. 
Currently, two licensed, single-antigen hepatitis A vaccines are available: Vaqta (Merck) and Havrix (GlaxoSmithKline). Vaqta’s efficacy is reported to be 100%, and Havrix’s, 94%. The immunity of hepatitis A vaccines appears to persist for at least 20 years in adults who are vaccinated with a two-dose schedule. Protection following natural infection appears to be lifelong and may be the same following vaccination. Vaccine titers from only one dose can persist for almost 11 years. Adult hepatitis A vaccine rates for the general population range from 5.4% to 13.4%.

The U.S. Housing and Urban Development’s (HUD) 2017 annual Homeless Assessment Report stated homelessness is increasing in the United States, with an estimated 3 million homeless persons (1% of the population). . This is a very difficult population for whom to provide medical care. A recent increase in hepatitis A virus outbreaks have occurred, caused primarily by spread among homeless persons, drug users, and men who have sex with men (MSM). Since January 2017, approximately 7,520 cases have been reported. Currently, homelessness is not considered a high-risk condition for a routine vaccination with hepatitis A vaccine. While little is known about hepatitis A immunity among homeless persons, there is a known high incidence in those who use drugs. Transmission is also related to crowding and poor hygiene. It is also unknown what percentage of the population must be vaccinated to provide herd immunity. Outbreaks of hepatitis are continuing and expensive to control.

Applying the EtR discussed above, the workgroup concluded that two doses of hepatitis A vaccines should be recommended for protection against hepatitis A among persons experiencing homelessness. ACIP voted to approve the recommendation for routine hepatitis A immunization of homeless persons.

Japanese encephalitis (JE)
In presentations at the last several ACIP meetings, the JE workgroup has updated the current recommendations. The group reported that the risk of JE disease in 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 (Valneva) at a cost of approximately $600 for the two-dose series. It is FDA licensed for age 2 months and older. Current ACIP recommendations for the vaccine are for those who plan to spend a month or longer in an endemic area during JE season or if traveling to high-risk endemic areas. The vaccine is not recommended for short-term travelers in urban areas or outside the JE season. 

In the EtR framework developed for JE vaccination, the workgroup concluded that since it is a low-risk disease and an expensive vaccine, health care providers should assess the following: a traveler’s risk for exposure; likelihood of further travel to JE-endemic countries; high morbidity and mortality of JE; availability of vaccine; the possibility, while low, of serious adverse events; the traveler’s personal perception of tolerance and risk; and the cost of the vaccine. Health care providers should inform travelers of other methods of prevention to help with the decision. 

For those for whom vaccination is determined to be needed, a proposed alternative is an accelerated schedule for adults aged 18 to 65 years of two doses administered 7 days apart. Those aged 17 years and older should receive a boost-er dose of 0.5 mL if the primary series was given more than 1 year previously. FDA has recently approved a booster dose for children aged 14 months and older, with the recommended dose being 0.25 mL for those aged 14 months through 2 years and 0.5 mL for those older than 3 years. A final vote is expected in February 2019.

Anthrax vaccine
A new anthrax vaccine (AV7909) consisting of anthrax vaccine absorbed ([AVA] Biothrax—Emergent BioSolutions) with an adjuvant (CPG 7909) is currently in Phase III studies. Preliminary results demonstrated an improved immune response when compared with the AVA alone. Two doses of this vaccine have been found to be comparable to three doses of the AVA vaccine. This is advantageous for rapid protection when used for postexposure prophylaxis along with antibiotics during an anthrax attack. In addition, the safety profile is similar to that of Biothrax. Additional studies are currently on-going.
Three FDA-approved antitoxins are currently available for treatment of inhalational anthrax, with two of the antitoxins, both monoclonal antibodies (mab), also indicated for postexposure prophylaxis. Raxibacumab (GlaxoSmithKline/Emergent BioSolutions) is a monoclonal antibody approved in 2012; anthrax immune globulin intravenous ([AIGIV] Anthrasil—Cangene) was approved in 2015; and obiltoxaximab (Anthim—Elusys Therapeutics) is a monoclonal antibody approved in 2016. 

These antitoxins do not induce an immune response for long-term protection. When AVA is given with the immune globulin AIGIV, the development of a protective immune response was reduced, making this a poor choice for postexposure prophylaxis. Anthrax mab antitoxins are indicated for use as postexposure prophylaxis when alternative therapies are not available. Protection is also significantly reduced with increasing time to intervention, so they must be administered within 12 to 18 hours of exposure. AVA along with raxibacumab antitoxin does not appear to affect immunogenicity (unknown with obiltoxaximab). If no alternatives for postexposure prophylaxis are available, the two mab antitoxins may be considered. 

Adult and childhood/adolescent schedule
The immunization schedules will be published in early February 2019. There have been several updates in ACIP recommendations since the 2018 schedules were published. Specifically, influenza recommendations now include the use of live attenuated influenza vaccine (LAIV); hepatitis B recommendations include the use of a new vaccine (Heplisav B—Dynavax), and hepatitis A use is now recommended for persons who are homeless. In response to feedback from a survey administered to providers, including pharmacists, the appearances of the schedules were also redesigned. The pregnancy column in the adult schedule had several color additions, including pink for delaying administration, orange for precautions, and white for no recommendation. There will be a harmonization with the child/adolescent schedule to reflect these changes. The committee voted to approve the schedules.

Vaccine supply
Hepatitis B vaccine produced by Merck is still not being distributed and will not be available through the end of 2019. GlaxoSmithKline and Dynavax will continue to supply adequate amounts for the current demand. 

GlaxoSmithKline’s Shingrix vaccine is expected to be delayed through 2018, and further increases in production are planned for 2019. More information is available at www.cdc.gov/vaccines/hcp/clinical-resoures/shortages.html. 

General recommendations
General Best Practices Guidelines are now available at www.cdc.gov/vaccines/hcp/acip-recs/index.htm. These guidelines and the website are regularly updated as revisions occur. Some recent changes include DTaP minimal interval changes, removal of some precautions to DTaP, minimal intervals for the two meningococcal B (MenB) vaccines, hepatitis A immune globulin and hepatitis A vaccine dose and administration changes, varicella vaccine contraindications and precautions, zoster vaccine dose, and contraindications for antiviral medications with LAIV. These changes are fully described at the website. 
New guidelines have also been developed for administration of live vaccines by health professionals who themselves have a labeled contraindication. There is no reason for the immunocompromised health care provider to avoid administering live vaccines.