HPV vaccine approved to age 45; Tdap best late in pregnancy
the FDA just approved extension of the age limits for HPV-9 valent vaccine to include men and women til age 45!! (see https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm622715.htm ).
Details: (from the FDA statement)
-- CDC estimates that there are 14 million Americans infected with HPV annually, 12,000 women are diagnosed with cervical cancer and 4,000 die from it
-- FDA's director for biologics noted: ”The Centers for Disease Control and Prevention has stated that HPV vaccination prior to becoming infected with the HPV types covered by the vaccine has the potential to prevent more than 90 percent of these cancers, or 31,200 cases every year, from ever developing.”
-- a study of 3200 women aged 27-45 (beyond the current limit of 26yo), followed 3.5 years, HPV 9-valent vaccine (Gardasil-9) was 88% effective in preventing the combo endpoint of: persistent HPV infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to the vaccine-covered HPV types
-- the utility of HPV vaccine for men is inferred from this study of women, along with the evidence of efficacy in younger men and immunogenicity data of 150 men aged 27-45 receiving the 3-dose vaccine
-- safety was evaluated for 13,000 men and women, with most common adverse effects: injection site pain, swelling and redness, and headaches
Commentary:
-- i could not find and review the above studies: the best i could find was https://www.merck.com/product/usa/pi_circulars/g/gardasil_9/gardasil_9_pi.pdf , with following info:
-- 3253 women 27-45 yo were in RCT (vaccine vs just the adjuvant), looking at combined endpoint of HPV 6-, 11-, 16-, or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS (adenocarcinoma in situ), and cervical cancer
-- followup 3.5 years after last HPV vaccine dose
-- efficacy of GARDASIL against the combined incidence of HPV 6-, 11-, 16-, and 18-related genital warts or cervical dysplasia was 95.0% (note: this combined efficacy was "driven primarily by the prevention of persistent infection", though no specific details were mentioned)
-- based on per-protocol efficacy, no statistically significant efficacy was demonstrated for GARDASIL in the base study for prevention of cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3), adenocarcinoma in situ (AIS) or cervical cancer related to HPV types 16 and 18; there was 1 case of CIN 2/3 observed in the GARDASIL group and 5 cases in the placebo group. The CIN 2 case in the GARDASIL group tested positive by PCR for HPV 16 and HPV 51.
-- so, from this study, it seems that there was really just a decrease in viral persistence, which is likely translatable to long-term prevention of bad clinical outcomes. but this should be still considered just a surrogate endpoint and may not necessarily lead to the anticipated outcomes
-- In the long-term extension of this study, subjects from Colombia (n=600) randomized to the GARDASIL group in the base study were monitored for HPV 6-, 11-, 16-, and 18-related genital warts or cervical dysplasia. The median follow-up post-dose 3 was 8.9 years with a range of 0.1 to 10.1 years over a total of 3,518 person-years. During the long-term extension phase, no cases of HPV 6-, 11-, 16-, or 18- related CIN (any grade) or genital warts were observed in the immunized population. [BUT, no comment on the number of cases in the non-immunized group or the statistical signficance of any difference]
-- immunogenicity of GARDASIL in men 27 through 45 yo: 150 men aged 27-45 received a 3-dose regimen of GARDASIL (0, 2, 6 months). Comparing Month 7 anti-HPV 6, 11, 16, and 18 to those of 16-26 year old boys and men in whom efficacy of GARDASIL had been established:
--GMT (geometric mean titer) ratios for HPV 6, 11, 16, and 18 were 0.82 (0.65- 1.03), 0.79 (0.66-0.93), 0.91 (0.72-1.13), and 0.74 (0.59-0.92), respectively [ie, the vaccine seems to have worked quite well, though, again, no access to the original study: what were their titers for these HPV types prior to getting the vaccine?? was this study in one specific site, where exposure to these HPV types was perhaps different from other places?? what were the demographics of those involved?? comorbidities??]
so, to me this is still a welcome addition to the indications for HPV vaccine:
-- this really reinforces the importance of vaccinating kids when they are young (eg ages 9-14, when the vaccine is more immunogenic and there are only 2 shots). see http://gmodestmedblogs.blogspot.com/2016/11/2-dose-hpv-vaccine-for-girls-and-boys.html
-- we should not forget the importance in men (though recommendations had been for ages 9-21 in normal risk men) : http://gmodestmedblogs.blogspot.com/2017/10/oral-hpv-in-men-and-oropharyngeal-cancer.html , noting dramatic increases in oropharyngeal cancer (in which men far outweigh women in incidence). this blog also argues for extending the age range for HPV vaccine
-- older articles have shown some decreased efficacy in women as they age (still under 27), likely related to their having gotten several HPV types prior to vaccination. BUT the vaccine still helps
-- a prior blog also argued for delaying the 3rd booster vaccine to improve immunogenicity (see http://gmodestmedblogs.blogspot.com/2018/02/new-adult-and-pedi-immunization.html ), again reinforcing the importance of getting kids when they are young
as with other FDA recommendations, this will still take awhile to filter down to us (ie, insurance companies covering it)
---------------------------------------
Tdap in pregnancy
A recent antibody level study suggested that giving Tdap vaccine to pregnant women at 30 weeks gestation optimizes the infants’ IgG levels in the first 2 months (see pregnancy Tdap jama2018 in dropbox, or doi:10.1001/jama.2018.14298, or https://jamanetwork.com/journals/jama/fullarticle/2706137 )
Details:
-- 626 women at Baylor College of Medicine in Texas were evaluated, half having received Tdap vaccines at mean gestation of 31 weeks, half not getting the vaccine (this was not an RCT, just a comparison between some who had and some who did not have the vaccine)
-- maternal age 30 (31 in immunized group, 29 if not), 40% white (48% if immunized, 34% if not)/25% black (17% if immunized, 36% if not)/5% asian, birth wt 3400gm, gestation 39 weeks (lowest 37/highest 42 weeks)
-- so, the immunized group was more likely to be older and white
-- primary outcome: geometric mean concentrations (GMC) of pertussis toxin antibodies in infant cord blood, comparing women immunized in third trimester vs non-immunized
-- secondary outcome: optimal gestation for immunization to achieve maximal neonatal antibody response
-- or the infants, they assessed antibody concentrations of >15, >30 and >45 IU/mL (15 is lowest quantifiable number, unclear exactly what the protective number should be)
-- they estimated the pertussis antibody titer in the infants at 2 months of age (at which point they are supposed to get their first pertussis vaccine) based on their initial titer at birth and the published half-life of passively acquired maternal levels (36 days)
Results:
-- primary outcome: those women having had the vaccine had higher pertussis antibodies in the newborn's cord blood, 47.3 IU/mL(42.1-53.2) vs 12.9 IU/mL (11.7-14.3), for a GMC ratio of 3.6 (3.1-4.2), p<.001, found also when controlling for maternal age, ethnicity and gestational age at delivery
-- pertussis toxin antibody concentrations, with p<0.001 for each analysis:
-- at least 15 IU/mL: 86% in vaccinated vs 37% in control, difference of 49% (42%-55%)
-- at least 30IU/mL: 72% in vaccinated vs 17% in control, difference of 55% (49%-61%)
-- at least 40IU/mL: 59% in vaccinated vs 12% in control, difference, of 47% (41%-54%)
-- secondary outcome: highest GMCs of pertussis toxin antibodies when Tdap vaccine given during weeks 27-30 and declined thereafter, reaching peak at week 30 with titer 57.3I U/mL (44.0-74.6)
-- the estimated GMC in infants at 2 months old was 11.8 IU/mL when mothers were immmunized and 3.2 IU/mL when not (p<0.001)
-- the estimated GMC in mothers getting the vaccine at 30 weeks was the highest in the infants, at 14.3 IU/mL
Commentary:
-- studies have shown that passive immunization works: epidemiologic studies in the US and UK have shown that Tdap given between 28-38 weeks gestation has resulted in a 91% decreased risk of pertussis in infants <3mo old
-- a few points of concern in interpreting the above data:
-- there are no specific data showing the level of pertussis antibody titer which is protective of infants
-- but, as opposed to older infants getting the pertussis vaccine starting at age 2 months, the above reflects the passive transfer of antibodies from mothers to the infants. this is really different from post-vaccination, which elicits an active antibody response (in these cases, there is more confusion about the appropriate antibody titer, since even with lower titers, exposure to pertussis might elicit an aggressive anamnestic response)
-- so, likely the higher titer in passive immunization, the better.
-- also, this was an observational study from a single research center. And we do not know the mothers' pre-immunization pertussis titers, which may vary significantly from one site to another
so, it does seem that vaccinating women with Tdap does work. this study just adds to this that it is likely to be optimal at 30 weeks' gestation. seems to me to be a reasonable refinement to the recommendation
geoff
Details: (from the FDA statement)
-- CDC estimates that there are 14 million Americans infected with HPV annually, 12,000 women are diagnosed with cervical cancer and 4,000 die from it
-- FDA's director for biologics noted: ”The Centers for Disease Control and Prevention has stated that HPV vaccination prior to becoming infected with the HPV types covered by the vaccine has the potential to prevent more than 90 percent of these cancers, or 31,200 cases every year, from ever developing.”
-- a study of 3200 women aged 27-45 (beyond the current limit of 26yo), followed 3.5 years, HPV 9-valent vaccine (Gardasil-9) was 88% effective in preventing the combo endpoint of: persistent HPV infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to the vaccine-covered HPV types
-- the utility of HPV vaccine for men is inferred from this study of women, along with the evidence of efficacy in younger men and immunogenicity data of 150 men aged 27-45 receiving the 3-dose vaccine
-- safety was evaluated for 13,000 men and women, with most common adverse effects: injection site pain, swelling and redness, and headaches
Commentary:
-- i could not find and review the above studies: the best i could find was https://www.merck.com/product/usa/pi_circulars/g/gardasil_9/gardasil_9_pi.pdf , with following info:
-- 3253 women 27-45 yo were in RCT (vaccine vs just the adjuvant), looking at combined endpoint of HPV 6-, 11-, 16-, or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS (adenocarcinoma in situ), and cervical cancer
-- followup 3.5 years after last HPV vaccine dose
-- efficacy of GARDASIL against the combined incidence of HPV 6-, 11-, 16-, and 18-related genital warts or cervical dysplasia was 95.0% (note: this combined efficacy was "driven primarily by the prevention of persistent infection", though no specific details were mentioned)
-- based on per-protocol efficacy, no statistically significant efficacy was demonstrated for GARDASIL in the base study for prevention of cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3), adenocarcinoma in situ (AIS) or cervical cancer related to HPV types 16 and 18; there was 1 case of CIN 2/3 observed in the GARDASIL group and 5 cases in the placebo group. The CIN 2 case in the GARDASIL group tested positive by PCR for HPV 16 and HPV 51.
-- so, from this study, it seems that there was really just a decrease in viral persistence, which is likely translatable to long-term prevention of bad clinical outcomes. but this should be still considered just a surrogate endpoint and may not necessarily lead to the anticipated outcomes
-- In the long-term extension of this study, subjects from Colombia (n=600) randomized to the GARDASIL group in the base study were monitored for HPV 6-, 11-, 16-, and 18-related genital warts or cervical dysplasia. The median follow-up post-dose 3 was 8.9 years with a range of 0.1 to 10.1 years over a total of 3,518 person-years. During the long-term extension phase, no cases of HPV 6-, 11-, 16-, or 18- related CIN (any grade) or genital warts were observed in the immunized population. [BUT, no comment on the number of cases in the non-immunized group or the statistical signficance of any difference]
-- immunogenicity of GARDASIL in men 27 through 45 yo: 150 men aged 27-45 received a 3-dose regimen of GARDASIL (0, 2, 6 months). Comparing Month 7 anti-HPV 6, 11, 16, and 18 to those of 16-26 year old boys and men in whom efficacy of GARDASIL had been established:
--GMT (geometric mean titer) ratios for HPV 6, 11, 16, and 18 were 0.82 (0.65- 1.03), 0.79 (0.66-0.93), 0.91 (0.72-1.13), and 0.74 (0.59-0.92), respectively [ie, the vaccine seems to have worked quite well, though, again, no access to the original study: what were their titers for these HPV types prior to getting the vaccine?? was this study in one specific site, where exposure to these HPV types was perhaps different from other places?? what were the demographics of those involved?? comorbidities??]
so, to me this is still a welcome addition to the indications for HPV vaccine:
-- this really reinforces the importance of vaccinating kids when they are young (eg ages 9-14, when the vaccine is more immunogenic and there are only 2 shots). see http://gmodestmedblogs.blogspot.com/2016/11/2-dose-hpv-vaccine-for-girls-and-boys.html
-- we should not forget the importance in men (though recommendations had been for ages 9-21 in normal risk men) : http://gmodestmedblogs.blogspot.com/2017/10/oral-hpv-in-men-and-oropharyngeal-cancer.html , noting dramatic increases in oropharyngeal cancer (in which men far outweigh women in incidence). this blog also argues for extending the age range for HPV vaccine
-- older articles have shown some decreased efficacy in women as they age (still under 27), likely related to their having gotten several HPV types prior to vaccination. BUT the vaccine still helps
-- a prior blog also argued for delaying the 3rd booster vaccine to improve immunogenicity (see http://gmodestmedblogs.blogspot.com/2018/02/new-adult-and-pedi-immunization.html ), again reinforcing the importance of getting kids when they are young
as with other FDA recommendations, this will still take awhile to filter down to us (ie, insurance companies covering it)
---------------------------------------
Tdap in pregnancy
A recent antibody level study suggested that giving Tdap vaccine to pregnant women at 30 weeks gestation optimizes the infants’ IgG levels in the first 2 months (see pregnancy Tdap jama2018 in dropbox, or doi:10.1001/jama.2018.14298, or https://jamanetwork.com/journals/jama/fullarticle/2706137 )
Details:
-- 626 women at Baylor College of Medicine in Texas were evaluated, half having received Tdap vaccines at mean gestation of 31 weeks, half not getting the vaccine (this was not an RCT, just a comparison between some who had and some who did not have the vaccine)
-- maternal age 30 (31 in immunized group, 29 if not), 40% white (48% if immunized, 34% if not)/25% black (17% if immunized, 36% if not)/5% asian, birth wt 3400gm, gestation 39 weeks (lowest 37/highest 42 weeks)
-- so, the immunized group was more likely to be older and white
-- primary outcome: geometric mean concentrations (GMC) of pertussis toxin antibodies in infant cord blood, comparing women immunized in third trimester vs non-immunized
-- secondary outcome: optimal gestation for immunization to achieve maximal neonatal antibody response
-- or the infants, they assessed antibody concentrations of >15, >30 and >45 IU/mL (15 is lowest quantifiable number, unclear exactly what the protective number should be)
-- they estimated the pertussis antibody titer in the infants at 2 months of age (at which point they are supposed to get their first pertussis vaccine) based on their initial titer at birth and the published half-life of passively acquired maternal levels (36 days)
Results:
-- primary outcome: those women having had the vaccine had higher pertussis antibodies in the newborn's cord blood, 47.3 IU/mL(42.1-53.2) vs 12.9 IU/mL (11.7-14.3), for a GMC ratio of 3.6 (3.1-4.2), p<.001, found also when controlling for maternal age, ethnicity and gestational age at delivery
-- pertussis toxin antibody concentrations, with p<0.001 for each analysis:
-- at least 15 IU/mL: 86% in vaccinated vs 37% in control, difference of 49% (42%-55%)
-- at least 30IU/mL: 72% in vaccinated vs 17% in control, difference of 55% (49%-61%)
-- at least 40IU/mL: 59% in vaccinated vs 12% in control, difference, of 47% (41%-54%)
-- secondary outcome: highest GMCs of pertussis toxin antibodies when Tdap vaccine given during weeks 27-30 and declined thereafter, reaching peak at week 30 with titer 57.3I U/mL (44.0-74.6)
-- the estimated GMC in infants at 2 months old was 11.8 IU/mL when mothers were immmunized and 3.2 IU/mL when not (p<0.001)
-- the estimated GMC in mothers getting the vaccine at 30 weeks was the highest in the infants, at 14.3 IU/mL
-- studies have shown that passive immunization works: epidemiologic studies in the US and UK have shown that Tdap given between 28-38 weeks gestation has resulted in a 91% decreased risk of pertussis in infants <3mo old
-- a few points of concern in interpreting the above data:
-- there are no specific data showing the level of pertussis antibody titer which is protective of infants
-- but, as opposed to older infants getting the pertussis vaccine starting at age 2 months, the above reflects the passive transfer of antibodies from mothers to the infants. this is really different from post-vaccination, which elicits an active antibody response (in these cases, there is more confusion about the appropriate antibody titer, since even with lower titers, exposure to pertussis might elicit an aggressive anamnestic response)
-- so, likely the higher titer in passive immunization, the better.
-- also, this was an observational study from a single research center. And we do not know the mothers' pre-immunization pertussis titers, which may vary significantly from one site to another
so, it does seem that vaccinating women with Tdap does work. this study just adds to this that it is likely to be optimal at 30 weeks' gestation. seems to me to be a reasonable refinement to the recommendation
geoff
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