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

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 betapapillomavirus es 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 .