Highlights of the Latest Meeting of the Advisory Committee On Immunization Practices
Three times a year a specialized group of medical and public health experts meet in Atlanta to review scientific data related to vaccine safety and effectiveness. Although most people are probably unaware that these meetings occur, this is not some clandestine group. Far from it actually. Meeting dates and proposed agendas are available in advance, all meetings are open to the public and available via webcast, public comments are accepted, and past meeting notes and slide presentations are accessible online.
What amazes me is that the 15 voting members, 8 ex officio members and 30 non-voting representatives of this group participate voluntarily. In addition to the three meetings per year, members serve in various work groups that are active all year long. Work groups review the latest studies on specific vaccines, as well as the safety and efficacy of those vaccines, in order to provide recommendations to the larger committee.
They work hard and take their responsibilities very seriously. And they should, because this group, known as The Advisory Committee on Immunization Practices (ACIP), has an enormous responsibility. They establish, update and continually evaluate all the vaccine recommendations that are made in the United States for infants, adolescents and adults. These guidelines are considered the gold standard among healthcare providers and health insurance coverage of vaccines is based on these recommendations.
If you’ve ever attended a meeting or tuned in to a live webcast, you know how thorough they are in their investigation of the science that is the driving factor behind every recommendation they make. Earlier this week, in their first meeting of 2016, ACIP members discussed a variety of vaccines to include HPV, meningococcal, influenza and Japanese encephalitis, as well as Zika virus. For those who were unable to attend the meeting or tune in via webcast, I would like to provide a brief recap of the major discussion items.
The discussion focused on the ongoing review of data comparing the immunogenicity of human papillomavirus (HPV) vaccine after a 2 dose schedule versus a 3 dose schedule.
As early as June 2014, the ACIP began reviewing data for 2 dose bivalent and quadrivalent HPV vaccines. The World Health Organization has been recommending a 2 dose schedule since 2014 for children starting the series before age 15 and most other countries who primarily administer bivalent or quadrivalent HPV vaccines are already using a 2 dose schedule. These 2 dose schedules are recommended in foreign countries for use with the bivalent and quadrivalent vaccines. Here in the U.S. the ACIP began recommending the 9-valent HPV vaccine, which provides protection from additional strains of HPV in February, 2015. Vaccination with 3 doses was recommended at that time.
In evaluating the possibility of reducing the number of doses from 2 to 3 here in the U.S., the ACIP reviewed data on the immunogenicity of a 2 dose versus 3 dose HPV vaccination schedule to determine whether a different schedule could provide similar, acceptable levels of protection in the months and years following vaccination as compared to what is expected with a 3 dose schedule. The Committee reviewed three studies comparing 2 doses versus 3 doses of the bivalent HPV vaccine, three studies comparing 2 doses versus 3 doses of quadrivalent vaccine (one from Canada, one from Mexico and a large trial from India), and preliminary findings from a ongoing study of 9-valent vaccine that is expected to continue for two more years.
Each study was conducted slightly differently and provided an extensive amount of data to consider. For instance, some studies differentiated between the timing of the doses, (such as 0, 6 month dosing and 0, 12 months dosing versus the 0, 6, 12 month interval that is currently recommended). Some studies also accounted for differences in gender, ages of administration of doses (for instance, young girls versus older women and girls versus boys). There was even data that differentiated between the seroconversion rates at different intervals after vaccination and among the antibody titers for the different HPV types.
The data appears to suggest that a 2 dose schedule may be a consideration moving forward. However, the ACIP’s HPV Work Group still needs to evaluate all the data in greater detail before they can present their recommendations for further discussion and approval by the entire ACIP Committee at a future meeting.
The Committee still needs to consider that completion of a 2 dose regimen would be important since the effectiveness of a single dose is known to be lower. Currently, completion rates for the 3 dose regimen remains suboptimal and there would be even less flexibility in a 2 dose regimen. Additionally, the duration of protection from a 2 dose 9-valent vaccine has not been determined, but is currently undergoing investigation. This type of data will likely need to be evaluated in comparison to a 3 dose schedule before proceeding with a change of recommendation.
A study released earlier this week suggests that we may be witnessing a herd effect with HPV vaccine. Despite only 40% of girls and 22% of boys being vaccinated, the rate of HPV infections among young women has plummeted by two-thirds since the introduction of the vaccine. Before altering the current recommendations, the Committee may also want to consider the comparative herd effect in a 2 dose versus 3 dose schedule.
It was noted that the vaccine manufacturer is seeking FDA approval of a 2 dose 9-valent HPV vaccine, which should be determined within the year. In the meantime, if the ACIP were to recommend a 2 dose schedule before the FDA review is complete, the recommendation would be considered off label. Although some may question an off label recommendation, the ACIP has made other off label recommendations when sufficient evidence suggests it is reasonable to do so.
The ACIP reviewed several post-approval studies of meningococcal serogroup B vaccine to further evaluate the vaccine’s safety and efficacy profile. Additionally, the Committee was presented with data from a mass immunization campaign that occurred in response to a large meningococcal serogroup B outbreak in Quebec, Canada. There was also discussion pertaining to a possible increased risk of meningococcal disease among HIV infected persons.
As background, it was noted that the ACIP issued a recommendation for meningococcal serogroup B vaccine in 2015 following FDA licensure. Prior to the licensure of the vaccine, the FDA approved special use of the vaccine in response to outbreaks of the disease on various college campuses. While both the ACIP and the FDA have previously reviewed the efficacy and safety data available from pre-licensure vaccine trials, and from the use of the vaccine in many countries that have licensed and administered the vaccine ahead of the U.S., the Committee will continue to review post-approval studies to ensure the vaccine’s safety and efficacy.
This week, the Committee reviewed four safety and immunogenicity studies, all of which demonstrated a high proportion of individuals who achieved a high consistency of response across the studies. The safety profile seemed consistent with the safety data at licensure and phase three studies confirmed that the vaccine elicits bacterial responses that correlate to protection against the four most prevalent strains circulating in the U.S., as well as 10 additional strains. The data continued to demonstrate broad protective response when used for both outbreak control and prevention of endemic disease.
Additionally, there was a review of a mass immunization campaign following a significant outbreak in Quebec, Canada. The data suggests direct protection during 18 months following vaccination with 100% vaccine effectiveness observed among the 47,115 vaccinated people and two cases among two unvaccinated adults. There was additional data presented on the safety profile and observational evidence pertaining to adverse events such as pain and fever post injection.
The meningococcal vaccine discussion also suggested that there is a growing body of evidence that supports an increased risk of meningococcal disease among HIV-infected persons. This is of particular interest since the ACIP doesn’t currently include HIV-infected persons on the list of people at high risk. This is largely due to evidence that suggests that the meningococcal vaccine offers suboptimal vaccine response and duration of protection among this particular demographic of HIV-infected persons. In contrast, the American Academy of Pediatrics does in fact recommend MenACWY vaccine for HIV infected persons ages 2 and up. So, while the Meningococcal Work Group seems supportive of adding a recommendation to include HIV infected persons, they will continue to review additional data and will report back to the full Committee at a future meeting.
During the public comment period of the meeting, Lynn Bozof from the National Meningitis Association, raised the concern that the public is having difficulty locating MenB vaccine. She provided anecdotal evidence that her member families seeking MenB vaccination for their children have had to make up to five calls to providers to gain access to the vaccine. She feared that less motivated families would simply give up. She asked that the ACIP consider the ramifications of their permissive Category B recommendation for MenB vaccination, which in her opinion does not carry the strength of a full Category A recommendation.
ACIP’s current recommendation as posted on the CDC website states that “Teens and young adults (16 through 23 year olds) may also be vaccinated with a serogroup B meningococcal vaccine (Bexsero® or Trumenba®), preferably at 16 through 18 years old. Two or three doses are needed depending on the brand.” “Preteens, teens, and young adults should be vaccinated with a serogroup B meningococcal vaccine if they are identified as being at increased risk of meningococcal disease.” This is quite different than the Category A recommendation for the vaccine to prevent the A,C,W and Y strains of meningococcal. The recommendation states that “all 11 to 12 year olds should be vaccinated with a single dose of a quadrivalent (protects against serogroups A, C, W, and Y) meningococcal conjugate vaccine (Menactra® or Menveo®)”. The small differences in recommendation types can make a big difference in the number of individuals who are offered the vaccine, have access to the vaccine and ultimately get vaccinated.
There were two significant discussions pertaining to influenza vaccine. First, the CDC announced that based on interim vaccine effectiveness data it appears that getting a flu vaccine this season has helped reduced the risk of having to go to the doctor because of flu by 59%. Additionally, data suggests that there is a very low rate of adverse reaction to flu vaccine in people who have egg allergy and that since the same reactions occur at the same rate in non-egg-allergic people, the ACIP will be removing egg allergy warnings for influenza vaccination.
The influenza surveillance data from this season indicates that influenza activity in the U.S. has been lower this season than in the last three seasons, and that there is a good match between the most common circulating viruses (A (H1N1) and B) which may explain why the vaccine is offering significant protection this season. It was also noted that there have been 13 pediatric deaths this season.
The Committee also learned that among the 73.7 million children in the U.S., 1.3% or approximately 958,100 children have some type of egg allergy. Current flu vaccine recommendations for those with allergy to egg are quite extensive, including a long algorithm which must be considered by vaccine administrators. The recommendation that children be monitored post vaccination or seek the advice of an allergist may result in parents avoiding influenza vaccine all together for their children. However, this may no longer need to be the case.
In the review of 27 published studies involving flu vaccine and egg allergy, most studies included patients with history of severe anaphylaxis with egg ingestion. These patients tolerated the vaccine without any serious reactions such as respiratory distress or hypotension. While there was a very low rate of minor reactions such as hives and mild wheezing, these reactions occurred in non-egg-allergic people at the same rate. Similarly, there was a one in one million chance of anaphylactic reaction to flu vaccine among egg-allergic people, which is the same rate in response to flu and other vaccines in non-egg-allergic people. The research suggests that there haven’t been serious reactions to flu vaccine in people with egg allergies because flu vaccines contain minimal egg ovalbumin and therefore are unlikely to cause a reaction in egg-allergic people. In fact, it was demonstrated that the manufacturers have actually over-estimated the amount of egg ovalbumin contained in both the IIV (injected) and LAIV (live attenuated/nasal) vaccines.
Based on the Committee’s review of this data, the ACIP voted to remove the precautions about IIV and LAIV flu vaccine for people with a history of egg allergy. The ACIP Influenza Work Group was tasked with developing the exact wording of the recommendation post-meeting, which will be approved for the 2016-2017 season. Stay tuned for the exact recommendation changes.
Japanese encephalitis vaccine:
The ACIP reviewed data on the current recommendation for travelers to receive Japanese encephalitis vaccination. Studies regarding the safety of the vaccine and duration were presented to the Committee and it was determined that there was insufficient data to spur the inclusion of a booster (2nd) dose of the vaccine. The latest data will however be included in an upcoming MMWR and further considered at a future meeting.
The Committee was given an overview of the international efforts to quell outbreaks of the Zika virus and develop a potential vaccine to protect against future infections worldwide. Collaboration among global experts was similar to the impressive response to the Ebola outbreaks and the conversation regarding the potential for a future vaccine was encouraging.