Assumptions about naturally acquired immunity after HPV infection

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HPV prevalence among HIV-negative women is not following the trend of observed data in our 24Feb20 calibration. There is uncertainty around naturally acquired immunity, and our assumptions might be prohibiting our ability to fit the observed data.

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Current assumptions:

• Only women develop type-specific, temporary, and partial natural immunity
• All women develop natural immunity after clearing HPV infection
• All ages benefit from natural immunity, but the extent of protection afforded by natural immunity increases linearly from the 20-24 age group to the 45-49 age group
• Natural immunity goes away at the same rate across all age groups (also this rate is based on only HPV-16)

Another note about this: natural immunity is type specific. However, we group HPV infections as 9v-type HPV and non-9v type ocogenic HPV. We therefore overestimate the protection provided by natural immunity.

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(Beacher, JID, 2016, Natural acquired immunity against subsequent genital Human Papillomavirus infection: A systematic review and meta-analysis)

• Natural immunity in women but not in men
• In women, pooled RR of HPV infection of 0.65 for HPV-16, 0.70 for HPV-18. Type-specific protection for combined measure of HPV-6/11/31/33/45/52/58 with a RR of 0.75.
• Duration of natural immunity unclear; didn't assess this Age varied considerably across different studies and were unable to evaluate potential effect modifier by age

(Safaeian, JID, 2018, Risk of HPV-16/18 infections and associated cervical abnormalities in women seropositive for naturally acquired antibodies: Pooled analysis based on control arms of two large clinical trials)

• Only a fraction (50%–70%) of women develop antibodies after natural infection
• Separate analysis within CVT and PATRICIA trials independently reported the protective role of naturally acquired HPV-16 antibodies in future HPV-16 detection. A protective role for naturally acquired HPV-18 antibodies in future HPV-18 detection was shown in CVT, but it was not clearly established in PATRICIA, due to limited power (lower numbers of incidently detected HPV-18 infections in PATRICIA than CVT). In this analysis, use pooled data from these trials

(Rosillon, Cancer Med, 2019, Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV-16/18 antibodies)

• cohort size of approximately 2700 women
• Naturally acquired antibodies can remain detectable for at least 4‐5 years after the initial infection.
• Correlation between naturally acquired antibodies to HPV‐16 (and to a lesser extent HPV‐18) and reduced risk of newly detected infection was demonstrated in younger women (15‐25 years) in the control arm of the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) (2014 paper). Here, we examined the risk of “newly” detected HPV infections and cervical abnormalities among women >25 years in relation to naturally acquired HPV‐16/18 antibodies in the control arm of the VIVIANE during a 7‐year follow‐up period.
• Risk of newly detected HPV‐16, 6‐month PI and ASC‐US+ was statistically significantly lower in seropositive vs seronegative women (HR = 0.56 and 0.28). Analysis for HPV‐16 incident infections and 12‐month PI also showed a somewhat lower risk in seropositive than seronegative women although the difference was not statistically significant (HR = 0.81 and 0.53). With regard to HPV‐18, we found the risk of newly detected infections and cervical abnormalities was lower in seropositive vs seronegative women, but not statistically significant (HR = 0.95 for incident infections, 0.43 for 6‐month PI, 0.31 for 12‐month PI, and 0.61 for ASC‐US+).
• This result agrees with the hypothesis that naturally acquired HPV antibodies probably provide only partial protection against subsequent infection with the same HPV type
• The association between seropositivity and the reduced risk of new infection was less in our study of 26+‐year‐old women than demonstrated in our study of younger women aged 15‐25 years in PATRICIA and in the Costa Rica Vaccine Trial. This low protective effect or even absence of protective effect in >25‐year‐old women could suggest waning of the natural immunity but it could also reflect reactivation of prior infection.
• In another analysis of the control cohort of the VIVIANE trial, the risk of detecting CIN after natural HPV infection in women aged >25 years was similar to that observed in women aged 15‐25 years from the PATRICIA trial. This observation suggests that there are little to no age‐related differences in the detection of natural HPV infection and their associated CIN lesions.