Primary Care Corner with Geoffrey Modest MD: 2-dose HPV vaccine for girls and boys

By Dr. Geoffrey Modest

On 10/19/16, the CDC recommended that 9 to 14 year olds receive only 2 doses of the 9-valent HPV vaccine at least 6 months apart, instead of the prior recommendation for 3 doses. But those who started the series between ages of 15 through 26 continue to need 3 shots (see http://www.cdc.gov/media/releases/2016/p1020-hpv-shots.html for the press release). Here is the article it was based on (see doi:10.1001/jama.2016.17615).

Details:

• Open-label, non-inferiority study done in 52 ambulatory sites in 15 countries, with 5 cohorts:
  • Girls aged 9 to 14, getting 2 doses 6 months apart (n= 301)
  • Boys aged 9 to 14, getting 2 doses 6 months apart (n= 301)
  • Girls and boys aged 9 to 14 getting 2 doses 12 months apart (n= 301)
  • Girls age 9 to 14 getting 3 doses over 6 months, the current recommendation (n= 301)
  • Adolescent girls and young woman aged 16 to 26 getting 3 doses over 6 months, acting as the control group (n= 314)
• Mean age 11, BMI 20, 60% white/17% Asian/10% black, 25% North America/20% Asian Pacific/30% Europe/15% Latin America/8% Africa
• Eligible 9-14 yo’s had to be generally healthy and not sexually active prior to enrollment. Those in the control group (age 16-26) had to be generally healthy with 4 or fewer lifetime sexual partners. All of the intervention groups were seronegative for each subtype prior to the 1^st dose of vaccination
• The primary endpoint was the antibody response to each of the HPV types, assessed one month after the last dose of vaccine

Results:

• More than 90% of participants in each cohort seroconverted to each HPV subtype
• HPV antibody responses in girls and boys given the 2 doses were not inferior to the control group (p < 0.001 for each HPV type).
• There was essentially no difference between boys’ and girls’ responses to the vaccine
• There was also no difference between those receiving the 2^nd dose after 6 months or after 12 months, though the antibody responses in those receiving the 2^nddose after 12 months were someone higher than after 6 months
• The antibody responses were roughly 2 to 3 times higher in the younger cohorts than the older control for each HPV type
• Post hoc analysis assessing antibody response 6 months after the last dose of vaccine declined in all of the cohorts, but the antibody responses remained non-inferior in the 2-dose regimens
• 22 participants had a serious adverse event, all not considered to be related to the vaccine. One person discontinued the study because of transient urticaria

Commentary:

• The 9-valent HPV vaccine provides protection against 7 high-risk HPV types responsible for 90% of cervical cancers or other anogenital cancers, as well as 2 other types responsible for 90% of genital warts.
• The WHO in 2014 changed their recommendations for girls aged 9 to 14 from a 3 dose to a 2 dose schedule (at 0 and 6 months).
• Other studies have suggested that a longer interval between the 1^st and 2^nd dose is more immunogenic, and that a 2^nd dose earlier than 5 months after the 1^st dose seems to be less effective; i.e. the second dose should not be before 6 months, and is more immunogenic at least in the short-term if given after 12 months as in the above study, or perhaps even later (the CDC press release only states that the second dose should be at least 6 months later)
• Other studies of also found that coadministration of the 9-valent HPV vaccine with diphtheria, tetanus, pertussis, polio, and meningococcal vaccines can be done at the same visit.
• This study did not have clear clinical outcomes, though it seems to me that antibody response is a reasonable surrogate marker for clinical protection. A prior blog (see https://stg-blogs.bmj.com/bmjebmspotlight/2015/04/01/primary-care-corner-with-geoffrey-modest-md-hpv-vaccine-recommendation-update/ , or see Joura EA. N Engl J Med 2015; 372: 711) dealt with the initial recommendations for the 9-valent vaccine, showing that not only was this vaccine immunogenic, it was also quite safe, and provided 7% efficacy in preventing >= CIN2 lesions. — And HPV vaccine is not only quite expensive, it is also very painful and requires more medical visits to do 3 vs 2 injections.
• It should be noted that there are no data showing what the minimum clinically-effective protective titer is for HPV vaccination
• The investigators will be following antibody persistence and the duration of protection over time.
• This study was designed to look at a younger cohort because of their increased HPV-vaccine immunogenicity, as documented in other studies (and confirmed in this study). It certainly seems reasonable that a subsequent study should look at the effectiveness of 2-dose regimens for those older than 14 and those who have been more sexually active/have evidence of prior infection by some of the HPV types.