Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination type replacement may occur, especially if different HPV types competitively interact during natural infection. There is little evidence that HPV type competition exists, but it is difficult to assess type interactions in observational studies. Randomized controlled trials (RCTs), originally designed to evaluate HPV vaccine efficacy, provide a good setting to evaluate type replacement.
Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and the PATRICIA trial (NCT001226810) – two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine – to compare cumulative incidence of non-protected HPV infections after 4 years of follow-up (oncogenic types 35, 39, 51, 52, 56, 58, 59, 68/73; non-oncogenic types 6, 11, 34, 40, 42, 43, 44, 53, 54, 66, 70, 74). In both trials, HPV DNA testing was conducted using the SPF10/DEIA - LiPA25 version 1 method and type-specific PCR for HPV16/18. In our primary analyses, incident infection was defined as an infection during follow-up (single time detection) that was not present during the vaccination phase (entry/6-month visits), or if present, that cleared during follow-up (single time clearance) before reappearing. Females were not considered at risk while infected with HPV types that the HPV-16/18 vaccine is suspected to confer protection against (HPVs 6, 11, 16, 18, 31, 33, 45, 51, and 74). These types were excluded from our grouped analyses of oncogenic and oncogenic/non-oncogenic HPV types, but we considered HPVs 6, 11, 51, and 74 in our individual-type analyses. Negative rate difference estimates were interpreted as evidence of type replacement if the associated 95% CI excluded zero.
After applying relevant exclusion criteria, 21,596 females (age 15 to 25 years) were included in our pooled analysis (HPV arm = 10,750, control arm = 10,846). Incidence rates (per 1000 infecton-years) were lower in the HPV arm than in the control arm for grouped oncogenic HPV types (rate difference = 1.6, 95% CI = 0.9 to 2.3) and for grouped oncogenic/non-oncogenic types (rate difference = 0.2, 95% CI = -0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed for any of the 20 types we evaluated; however, a nominal protective effect was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as non-oncogenic types 6 and 70.
HPV type replacement does not occur among vaccinated individuals within 4 years, and is unlikely to occur in populations comprised of vaccinated individuals.
Submitted on behalf of the CVT and PATRICIA study groups; *Joint senior authors