New adult and pedi immunization protocol; and HPV more immunogenic if delayed booster doses

The Advisory Committee on Immunization Practices, ACIP, of the CDC just released the new 2018 immunization schedule for adults (see immunization adult 2018 AIM2018 in dropbox, or http://annals.org/aim/fullarticle/2671913/recommended-immunization-schedule-adults-aged-19-years-older-united-states ). There is the usual: an updated grid for recommended immunizations by different ages, and another by medical conditions. Just a few changes from last year:

Recommendations:

--RVZ (recombinant zoster vaccine) added:

    --recommended to give at age 50

    --give even if already immunized by the old varicella vaccine (renamed ZVL, zoster live vaccine), but should be at least 2 months after ZVL, or if have had zoster in the past

    --2 doses, 2-6 months apart

    --can give either RZV or ZVL at age 60, but RZV is preferred [this is a bit strange to recommend ZVL at all, since they recommend RZV in those who already had ZVL…..]

    --there are some unknowns about RZV (so the ACIP has no recommendation), including pregnancy; confirmed or suspected immunodeficiency including HIV, malignancy, or immunocompromising therapies (these people were excluded from the studies, so unclear about effectiveness/safety). But RZV still recommended for those on low-dose immunosuppressives, are anticipating immunosuppression or have recovered from an immunosuppressive illness. And RZV is recommended for chronic medical conditions (diabetes; chronic heart, lung, liver dz; functional/anatomical asplenia; complement deficiencies).

    --see blog http://gmodestmedblogs.blogspot.com/2017/10/fda-approves-new-zoster-vaccine.html for brief review of the studies supporting RZV, and a few concerns, such as the durability of the vaccine over time, and the fact that the 2 big studies were done by the same drug-company sponsored group. but overall RZV seems to be a much better vaccine than the old one

--MMR:

    ​--for those at risk for mumps (eg, in an outbreak) who have had up to 2 doses of MMR, ACIP recommends a 3rd MMR.

 Commentary:

--they are basing the MMR recommendation on the MMWR report https://www.cdc.gov/mmwr/volumes/67/wr/mm6701a7.htm​ , which shows that a third dose of MMR decreases mumps attack rates.  these studies were done in students and younger people. unclear to me whether this recommendation applies to those considered immune to mumps by being born before 1957 or having laboratory evidence of immunity. [though the studies did not include these groups, my guess is that they have longterm protection and don't need the vaccine]

--as a background: the US is not particularly good in adult vaccination rates: influenza has increased a bit to 44.8% of adults, Tdap 23.1%, zoster in those >60yo at 30.6%

--kids have higher vaccination rates for several reasons: lots of routine health care visits, more emphasis on prevention/vaccination in the visits and more expected by patients and providers, vaccination requirements for school, more likely to have health care coverage, and more developed systems overall to immunize kids. Adults tend to have fewer exposures to the system (at least as healthy middle-aged ones), are more likely to have chronic medical problems which takes time away from preventive care issues (and the mindset of the clinicians and patients is to focus on the active problems), and adults are more likely not to have adequate (or any) health insurance coverage.

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ACIP/CDC immunization recommendations for children and adolescents (see https://www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html#schedule  for the recommendation schedule (in color), catch-up schedule, and vaccines for kids with medical conditions; http://pediatrics.aappublications.org/content/early/2018/02/02/peds.2018-0083​ from the Am Acad of Pediatrics review of it. Almost no changes from last year, but some minor reorganization. the few changes:

--MMR: as noted in the adult schedule above, if there is a mumps outbreak, those >12 months old who have received 2 or fewer doses of MMR should get an extra dose

--Flu: live attenuated flu (LAIV) is off the list

--Hep B: if infant < 2000 grams is born to HBsAg-negative mother, give vaccine at chronological age of 1 month or at hospital discharge. if weight is >2000 gm, give within 24 hours of birth

a study found that delaying the booster doses of HPV vaccine improved antibody titer response (see hpv 4-valent better resp if delayed dosing Vaccine2018 in dropbox, or doi.org/10.1016/j.vaccine.2017.12.042 ). (thanks to Rebecca Perkins for bringing this to my attention)

Details:

--the original recommendation for HPV vaccine was a dosing schedule of 0, 2 and 6 months

--1321 girls aged 9-17 given 4-valent HPV vaccine (HPV types 6,11,16,18)  in 6 US states from 2010-2012

--mean age 14, 39% white/51% black/7% multi-racial, BMI 24

--the girls were divided into 4 groups:

    --group 1 (control): 2nd dose on time (within 51-70 days of dose 1); 3rd dose on time (within 106-137 days of dose 2)

    ​--group 2: dose 2 on time, dose 3 late (>240 days after dose 2)

    --group 3: dose 2 late (>120 days after dose 1), dose 3 on time

    ​--group 4: both doses late

--blood drawn at 1 month and 6 months after the 3rd dose

--those in groups 1 and 3 (with 3rd dose on time) had blood drawn 4 months after the last dose

Results:

--antibody responses at 1 month after dose 3:

    --group 2 (dose 2 on time, but dose 3 late): dramatically improved antibody response for all 4 HPV types, compared to all other scenarios

--antibody responses at 6 months after dose 3:

    --group 2 (dose 2 on time, but dose 3 late): dramatically improved response for all 4 HPV types, compared to all other scenarios

    ​--groups 3 and 4 (delayed 2nd dose, and delayed both doses) were better than those getting the vaccine on time, except for HPV18 where getting a late 2nd dose was equivalent to getting all doses on time.

--synthesis: 

    --the best antibody response at both 1 and 6 months after the last dose of vaccine was in the group getting the second dose on time (within 51-70 days after 1st dose) but then delayed 3rd dose (>240 days after second dose). 

    --the next best (and only by the 6th month antibody titer check) was getting the 2nd dose late (>120 days after 1st one) and the 3rd dose late (>240 days after second dose)

    --but, all of the scenarios of getting late doses were at least as good as getting all of the doses on time

Commentary:

 --so, by this observational study, it seems that we should be waiting a bit longer for the 3rd dose. this is consistent with the finding in 9-14 yo's and the 2 dose sequence: there was a higher antibody response after 12 months than the recommended >6 month interval by the ACIP. see http://gmodestmedblogs.blogspot.com/2016/11/2-dose-hpv-vaccine-for-girls-and-boys.html 

--also, of note, community-based studies suggest that the average actual intervals are about 6 months between doses 1 and 2, then about 11 months between doses 2 and 3. (eg the North Carolina Immunization Registry found that on-time dosing was around 25%, and that is of the 55% who actually completed the series), per Tan W. Vaccine 2011; 29 (14): 2548.​

--a prior study in college students confirmed HPV-4 immunogenicity with a schedule of 0, 2, and 12 months; also found non-inferiority in those getting their 3rd shot 24 months after the first one

--one concern with such an observational study as the above one (vs an RCT) is: are there unexpected differences between the kids who actually got the vaccines on time vs the ones who were late? (eg, do those kids/parents who are really organized, perhaps a tad anal compulsive, have kids with deficient immune systems?? perhaps analogous to the hygiene hypothesis with allergies where those who are too bacteria-phobic have more allergies?? 😊😊). other issues:

    --does this apply to those getting HPV-9 (though HPV-4 does have the most important HPV types)?

    ​--does the antibody titer necessarily translate into clinical risk or protection? it seems to be a pretty logical assumption/extension that continued high antibody response is clinically  protective long-term, since antibody response in the short-term seems to be clinically protective.  but what about waning antibody response???  there was an interesting report of 17,622 women vaccinated at day 1, months 2 and 6 with HPV-4 vaccine, but with actual intervals up to 48 months, finding that though 39.7% were seronegative against HPV 18, clinical efficacy against HPV 18-related disease remained remarkably high at 98.4% vs a quite high infection rate in the control group (see Joura EA. Vaccine 2008; 26 (52): 6844), ie they had a clinically important anamnestic response for HPV-18 despite negative titers (HPV 18 causes about 20% of cases of cervical cancer).

so, this study confirms that those kids who have interrupted HPV vaccine schedules do not need to have their vaccines restarted. but, especially in light of the low % of kids who actually complete the full series, this study also reinforces the practice of immunizing kids when they are 9 or 10 years old, when there are only 2 shots, they are less likely to have had sex/contract HPV, and they tend to see their primary care clinicians more often than in later teen years.

see http://gmodestmedblogs.blogspot.com/search?q=hpv for an array of blogs on HPV