ACIP assesses data on intranasal influenza vaccine, cholera vaccine, and more
Highlights of June meeting summarized
CDC’s Advisory Committee on Immunization Practices (ACIP) addressed recommendations for use of the intranasal live attenuated influenza vaccine (LAIV), the new cholera vaccine, and much more at its June 22–23, 2016, meeting. As APhA’s representative to ACIP, I prepared this highlights summary for APhA. Complete minutes of the meeting will be published on CDC’s National Center for Immunization and Respiratory Diseases (NCIRD) website at www.cdc.gov/vaccines/acip/index.html.
LAIV efficacy assessed
This past influenza season peaked in March, which is later than most previous seasons. CDC reported that A(H1N1pdm09) was the predominant strain, along with both B viruses. The overall vaccine effectiveness (VE) against medically attended influenza was 47%, and the VE against A(H1N1pdm09) was 41%. VE against all influenza subtypes in children aged 2 years to 17 years was 63% for the inactivated influenza vaccine (IIV) compared with only 3% for the LAIV. When LAIV was evaluated against specific types, VE was negligible for type A(H1N1pdm09) and the B/Yamagata strains. In younger children aged 2 years to 8 years, VE against type A(H1N1pdm09) strain was even worse.
CDC stressed that the quadrivalent LAIV offered no protection against A(H1N1pdm09) in children during this last season and the previous two seasons. These results coincided with the change from the trivalent LAIV to quadrivalent LAIV. Possible causes of the LAIV’s lack of effectiveness include poor performance of the A(H1N1pdm09) vaccine strain in the nasal formulation, potential interference by the additional B virus in the quadrivalent formulation, or changes in the percentage of children previously unvaccinated in the early seasons compared with this most recent season (which perhaps caused the live vaccine to be unable to replicate).
Results of the ICICLE (Influenza Clinical Investigation for Children) clinical study presented by AstraZeneca differed from the CDC surveillance data presented above. AstraZeneca reported that LAIV’s VE was 46% and IIV’s VE was 65%. The study was designed similarly to the CDC study, except that additional respiratory viruses were tested from the nasal swabs. Another study, conducted in England, reported a VE of 57.6% for LAIV, and one in Finland showed a VE of 46% for LAIV. There was no explanation for why these results differed from the CDC data.
FDA, upon reviewing the data, has decided not to act against LAIV until more information is obtained. Based on CDC’s LAIV effectiveness studies, ACIP voted to state: “In light of the evidence for poor effectiveness of LAIV in the United States over the last three influenza seasons (2013–2016), for the 2016–17 season, the ACIP makes the interim recommendation that LAIV should not be used.”
Other influenza-related updates
Safety and immunogenicity of FluLaval (GlaxoSmithKline) for use in children aged 6 to 35 months was presented. The vaccine is currently approved for children aged 3 years and older. The only influenza vaccine approved for infants and children aged 6 months to 3 years is Fluzone (Sanofi-Pasteur). FluLaval Quadrivalent was studied in this age group, but researchers used a higher dose (i.e., 0.5 mL, with 15 ug HA from all four strains). The geometric mean titers (GMTs), as well as the adverse rate comparisons, were similar to those of Fluzone (i.e., the noninferiority objective was met). Use of this vaccine in children aged 6 months to 3 years will be discussed in future meetings.
Flucelvax Quadrivalent (Seqirus), a cell based–derived vaccine approved for patients 4 years of age and older, was FDA approved on May 23, 2016. The vaccine’s immune response criteria and safety data were noninferior to those of the trivalent vaccine.
The Vaccine Adverse Event Reporting System (VAERS) for the 2015–16 influenza season did not show safety concerns for any influenza vaccine. Surveillance for the next influenza season will include new vaccines such as Fluad (Adjuvanted) (Novartis Vaccines and Diagnostics Limited) and Fluzone Intradermal Quadrivalent (Sanofi-Pasteur). Vaccine surveillance for Guillain–Barré syndrome reported 7.25 cases per million IIV doses (5.45 cases per million doses was the average for the last three seasons), and monitoring will continue next year. The Vaccine Safety Datalink (VSD) data demonstrated that the relative risk for Guillain–Barré ranged between 3.0 and 3.67 during this past season compared with 1.39 during the 2014–15 season. This increase was statistically significant compared with recent previous seasons but was similar to that of several earlier seasons.
The 2016–17 influenza recommendations will also include information decided at previous ACIP meetings: vaccination recommended for all persons aged 6 months and older, minor changes in timing language, and egg allergy changes. In addition, new vaccines will be added (e.g., Fluad and Flucelvax), along with age changes for existing products.
Human papillomavirus (HPV) vaccines
Merck submitted an application to FDA earlier this year for a two-dose schedule of HPV-9 (Gardasil 9) for use in 9- to 14-year-olds. The World Health Organization (WHO) has recommended two-dose schedules for HPV-2 and HPV-4 in other countries if the vaccine is administered before 15 years of age. Merck’s data, presented at the February ACIP meeting, showed that a noninferiority antibody response occurred after two doses (at 0 and 6 months or 0 and 12 months) in 9- to 14-year-olds compared with the standard three-dose schedule at 0, 2, and 6 months in 16- to 26-year-olds. Previous studies demonstrated a high rate of seroconversion after vaccination, higher antibody titers after vaccination than after natural infection, and vaccination in younger ages resulting in the highest titers. The 6-month dose (booster) is very important for adequate immunological response.
Many trials of three-dose schedules for HPV vaccines (primarily HPV-2 and HPV-4) have been performed and evaluated for length of protection. Very few cases of HPV infection have occurred following vaccination over a 10-year period; other trials are ongoing or planned. The immunogenicity of HPV vaccines is very good, with seroconversion following vaccination approximately 97%.
A study presented at the February 2016 ACIP meeting showed that titers drawn 1 month after completion of a two-dose series in girls aged 9 to 14 years was similar to titers in women aged 15 to 25 years after a three-dose series. The studies are ongoing, but long-term protection data are not yet available for the two-dose schedules. A cost-effectiveness evaluation demonstrated that many variables can affect the outcomes and that the two-dose schedule must protect for more than 20 years before it is more cost-effective than a three-dose series.
Studies performed in other countries have been evaluated by the workgroup; however, the studies differed in type of analysis, type of study performed, vaccine used, interval of vaccine given, and endpoints. No studies have been conducted on use of the HPV-9 vaccine. Ten of the studies found that two doses were not as effective as three doses; however, most were trials of 0 and 1 month and 0 and 2 month schedules. Four of the trials were a 0- and 6-month schedule trial; of these, one showed that this longer schedule was effective, and three suggested that this longer interval was better than the shorter schedules.
The workgroup is considering a change in the ACIP recommendations. HPV vaccination should be administered at age 11 or 12 years. A two-dose series, with the second dose administered 6 to 12 months after the first, may be recommended for ages 9 to 14 years. If the second dose is given less than 6 months after the first, a third dose should be administered a minimum of 6 months after the first. Persons receiving the vaccine after age 15 should receive a three-dose series at 0, 1 to 2, and 6 months. Immunocompromised patients of any age should receive the three-dose series. These are only considerations and should not be used in practice at this time; a vote will occur at a future meeting after more data are evaluated.
GlaxoSmithKline has decided to withdraw its 2vHPV vaccine from the U.S. market by November 2016, and Merck will withdraw its HPV-4 vaccine by the end of 2016, leaving only the HPV-9 vaccine available in the United States.
On June 10, 2016, FDA approved Vaxchora (Pax Vax Bermuda), the only vaccine available to prevent cholera caused by serogroup 01, the predominant serotype around the world (99%). It was given fast track and priority review.
Cholera, a watery, diarrheal disease caused by the Vibrio cholera bacteria, is rare in the United States but common in parts of the world where water- and sewage-treatment programs are inadequate. Approved for adults aged 18 to 64 years, the vaccine is a single oral dose given at least 10 days before travel.
In one study, the vaccine demonstrated 90% efficacy at 10 days and 80% after 3 months. Its most common adverse effects were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite, and diarrhea. No data are available on use of the vaccine in pregnant or breastfeeding women, immunocompromised persons, or children. In addition, there are limited data on vaccine shedding; however, an older formulation did show shedding. There is also very limited information on the duration of protection beyond 3 to 6 months for this vaccine. Revaccination studies have not been performed.
CDC recommendations for use of the vaccine still include the need for safe food and water precautions. While vaccination is not recommended for most travelers, clinicians should evaluate risk of exposure to a cholera infection and individual risk factors that would indicate poor clinical outcomes if a patient is infected. These factors would include travelers who are unable to follow safe food and water measures, health care workers who may be exposed while treating patients, travelers without access to rapid medical care, those with low gastric acidity (including patients on chronic medications for stomach acidity), persons with type “O” blood (increased risk for cholera gravis), and travelers with chronic medical conditions (e.g., heart or kidney disease) who would tolerate dehydration poorly.
ACIP felt that the recommendation should be simplified to state that the vaccine should be recommended to patients who are traveling to areas of active toxigenic V. cholera transmission. The recommendation was approved by committee vote.
FDA approved a change to the meningococcal group B (MenB; Trumenba—Pfizer) label on April 14, 2016. A two-dose schedule (0 and 6 months) was approved along with the three-dose schedule (0, 1 to 2, and 6 months). The choice depends on risk of exposure and the patient’s susceptibility to meningococcal B disease. Data from immunological studies show similar titers and safety for the two- and three-dose schedules. Current ACIP recommendations state that either Trumemba or the Bexsero (GlaxoSmithKline) meningococcal group B vaccine should be given to all persons older than 10 years of age who are at increased risk, and it may be administered to adolescents according to clinician judgment.
A review of study results showed that the two-dose series had similar GMTs to the three-dose series; however, the greater-than-fourfold rise in human complement serum bactericidal assay titers were lower in the two-dose series. CDC felt that for outbreaks, a three-dose series should still be used and that healthy adolescents should receive a three-dose schedule because it maximizes the response and takes the same amount of time (6 months) to complete as the two-dose series. The workgroup suggested that if a person receives a second dose more than 6 months after the first, then no additional doses are needed. No vote was taken at this time. More information will be presented at the October meeting, including data on antibody persistence and the impact of vaccination on carriage.
ACIP currently has no recommendation for the use of meningococcal vaccine (Men ACYW-135) in patients with HIV. Recent studies from around the world have shown an increased risk of meningococcal disease in these individuals. A cost-effective analysis showed that the cost per quality-adjusted life year (QALY) saved for vaccinating all age groups with HIV was $732,000, compared with $212,000 for vaccinating all adolescents. A Grading of Recommendations, Assessment, Development, and Evaluations analysis showed that the evidence for benefit was low. Data presented at a previous ACIP meeting demonstrated that the sero-response of vaccination in 2- to 10-year-olds infected with HIV is low and that the immune response wanes rapidly. Despite these data, the workgroup recommended that patients with HIV who older than age 2 months should be added to the high-risk group that gets routine Men ACYW-135 vaccination.
Respiratory Syncytial Virus (RSV) vaccine
A new ACIP workgroup has been formed to discuss RSV and to develop recommendations for use of RSV vaccine. Most often, RSV causes upper respiratory infections that are more severe than the common cold. It has two major subgroups: A and B. Humans are the only source of transmission, and the virus is spread by close contact. Incubation is 4 to 6 days, with viral shedding for 3 to 8 days, but shedding can occur for up to 4 weeks.
RSV is a major cause of lower respiratory tract disease in infants and children, with studies showing that almost all children have been infected by age 2 years. Unfortunately, no vaccine is available for this age group. An older vaccine (formalin inactivated) was tested in the late 1960s, but it made lower respiratory tract infections worse in children when they became infected with RSV. Different types of vaccines appear to be necessary for different age groups. People older than age 60 years are also regularly infected with RSV, with approximately 180,000 hospitalizations per year. A new subunit vaccine targeting patients aged 60 and older is under development (Phase III trials).
Various other vaccines are in Phase II to III trials at this time.
Tdap vaccine in pregnancy
A review of the safety of the tetanus–diphtheria–acellular pertussis (Tdap) vaccine used during pregnancy was presented. In October 2011, ACIP recommended use of Tdap in every pregnancy. No unexpected safety concerns were noted in this group through VAERS. A study using the VSD to look for birth defects associated with Tdap showed no increased risk of birth defects following Tdap vaccination. Another study showed that moderate to severe injection-site pain occurred more frequently among pregnant women (18%) compared with nonpregnant women (11%) but was still within the rates of expected reactions.
ACIP recommendations for both hepatitis vaccines (i.e., A and B) are old, dating back to 2005 and 2006. The hepatitis workgroup is developing a new recommendation document to include changes that have occurred, including the addition of Twinrix (GlaxoSmithKline), use of hepatitis B vaccine in patients with diabetes, new recommendations for postexposure management for health care workers, and recommendations for mothers and their infants who are infected with hepatitis B.
Laboratory containment of poliovirus type 2
There have been only 16 cases of polio in 2016 (11 in Pakistan and 5 in Afghanistan). To minimize poliovirus facility-associated risk, the WHO Global Action Plan plans to destroy as much virus as possible and transfer any remaining virus to an “essential” laboratory facility. Currently, 122 laboratories in the United States have wild polio viruses (WPV). The first approach to containment is to contain WPV type 2, which had been eliminated as a disease. Surveys have been sent to determine where the WPV type 2 virus is stored. The overall goal is to have full containment of all types by 2019.
ACIP’s next meeting is scheduled for October 19–20, 2016.