Factors impacting protective immunity conferred by vaccination with adeno-associated virus-like particles displaying human papillomavirus L2 residues 17–36

Abstract

ABSTRACT A phase I study was conducted in 20 healthy subjects with 20 µg adeno-associated virus 2 (AAV2)-like particles displaying L2 residues 17–36 of both human papillomavirus (HPV) type 16 and HPV31 (AAVLP-HPV) or placebo. AAVLP-HPV vaccination was well tolerated and induced a modest L2-specific serum antibody titer that neutralizes HPV16, HPV31, and HPV5 in vitro. Here, we show that upon passive transfer into naïve mice, the sera from a subset of patients vaccinated with AAVLP-HPV conferred protection against HPV16, HPV31, and HPV5, but not HPV76. HPV16-naïve patients required three AAVLP-HPV doses to develop protection, whereas previously exposed individuals achieved protection after two doses and exhibited higher L2-specific and neutralizing antibody titers. The avidity of the L2-specific antibody response was low, but broadly cross-reactive. Prior exposure to AAV2 compromised the strength and duration of the L2 neutralizing antibody response, as well as protective immunity against HPV16, suggesting original antigenic sin. AAVLP-HPV induced high AAV2 neutralizing titers after one vaccination in AAV2-exposed or three in AAV2-naive patients. Thus, prior HPV and AAV2 infections impact the interpretation of AAVLP-HPV immunogenicity. IMPORTANCE HPV is among the most prevalent sexually transmitted infections. Persistent infection with a high-risk genotype (hrHPV) can cause cervical and other anogenital, and oropharyngeal cancers. There are a dozen hrHPV genotypes, HPV16 being the dominant type in these cancers; only ≤7 are targeted by licensed HPV vaccines. Ten intermediate-risk genotypes are also found in small proportions of cervical cancers. HPV6 and HPV11, while commonly associated with benign genital warts, can be carcinogenic in humans. The HPV+ cancer burden is highest in developing countries where cervical screening and vaccination rates are low, resulting in >500,000 cervical cancer cases annually. The plethora of skin-tropic HPVs are transmitted non-sexually and generally cause benign, self-limiting infections, but a subset of betapapillomaviruses is associated with cutaneous squamous cell carcinoma in epidermodysplasia verruciformis and immunocompromised patients. A simple, low-cost vaccine preventing infection by all of these medically significant HPV types is needed. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT03929172. HPV is among the most prevalent sexually transmitted infections. Persistent infection with a high-risk genotype (hrHPV) can cause cervical and other anogenital, and oropharyngeal cancers. There are a dozen hrHPV genotypes, HPV16 being the dominant type in these cancers; only ≤7 are targeted by licensed HPV vaccines. Ten intermediate-risk genotypes are also found in small proportions of cervical cancers. HPV6 and HPV11, while commonly associated with benign genital warts, can be carcinogenic in humans. The HPV+ cancer burden is highest in developing countries where cervical screening and vaccination rates are low, resulting in >500,000 cervical cancer cases annually. The plethora of skin-tropic HPVs are transmitted non-sexually and generally cause benign, self-limiting infections, but a subset of betapapillomaviruses is associated with cutaneous squamous cell carcinoma in epidermodysplasia verruciformis and immunocompromised patients. A simple, low-cost vaccine preventing infection by all of these medically significant HPV types is needed. This study is registered with ClinicalTrials.gov as NCT03929172.