Jagu Subhashini, Karanam Balusubramanyam, Wang Joshua W, Zayed Hatem, Weghofer Margit, Brendle Sarah A, Balogh Karla K, Tossi Kerstin Pino, Roden Richard B S, Christensen Neil D
Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA.
Biomedical Sciences Program, Health Sciences Department, Qatar University, PO Box 2713, Doha, Qatar.
Vaccine. 2015 Oct 13;33(42):5553-5563. doi: 10.1016/j.vaccine.2015.09.005. Epub 2015 Sep 15.
Vaccination with the minor capsid protein L2, notably the 17-36 neutralizing epitope, induces broadly protective antibodies, although the neutralizing titers attained in serum are substantially lower than for the licensed L1 VLP vaccines. Here we examine the impact of other less reactogenic adjuvants upon the induction of durable neutralizing serum antibody responses and protective immunity after vaccination with HPV16 and HPV31 L2 amino acids 17-36 inserted at positions 587 and 453 of VP3, respectively, for surface display on Adeno-Associated Virus 2-like particles [AAVLP (HPV16/31L2)]. Mice were vaccinated three times subcutaneously with AAVLP (HPV16/31L2) at two week intervals at several doses either alone or formulated with alum, alum and MPL, RIBI adjuvant or Cervarix. The use of adjuvant with AAVLP (HPV16/31L2) was necessary in mice for the induction of L2-specific neutralizing antibody and protection against vaginal challenge with HPV16. While use of alum was sufficient to elicit durable protection (>3 months after the final immunization), antibody titers were increased by addition of MPL and RIBI adjuvants. To determine the breadth of immunity, rabbits were immunized three times with AAVLP (HPV16/31L2) either alone, formulated with alum±MPL, or RIBI adjuvants, and after serum collection, the animals were concurrently challenged with HPV16/31/35/39/45/58/59 quasivirions or cottontail rabbit papillomavirus (CRPV) at 6 or 12 months post-immunization. Strong protection against all HPV types was observed at both 6 and 12 months post-immunization, including robust protection in rabbits receiving the vaccine without adjuvant. In summary, vaccination with AAVLP presenting HPV L2 17-36 epitopes at two sites on their surface induced cross-neutralizing serum antibody, immunity against HPV16 in the genital tract, and long-term protection against skin challenge with the 7 most common oncogenic HPV types when using a clinically relevant adjuvant.
用次要衣壳蛋白L2(特别是17 - 36中和表位)进行疫苗接种可诱导产生广泛保护性抗体,尽管血清中达到的中和效价比已获许可的L1病毒样颗粒(VLP)疫苗低得多。在此,我们研究了其他免疫原性较低的佐剂对分别插入腺相关病毒2样颗粒[AAVLP(HPV16/31L2)] VP3的587位和453位的HPV16和HPV31 L2氨基酸17 - 36进行疫苗接种后诱导持久中和血清抗体反应和保护性免疫的影响。小鼠以几种剂量单独或与明矾、明矾和MPL、RIBI佐剂或Cervarix制剂一起,每隔两周皮下接种三次AAVLP(HPV16/31L2)。在小鼠中,将佐剂与AAVLP(HPV16/31L2)一起使用对于诱导L2特异性中和抗体以及抵抗HPV16阴道攻击的保护作用是必要的。虽然使用明矾足以引发持久保护(末次免疫后>3个月),但添加MPL和RIBI佐剂可提高抗体效价。为了确定免疫广度,用AAVLP(HPV16/31L2)单独、与明矾±MPL或RIBI佐剂制剂对兔子进行三次免疫,收集血清后,在免疫后6或12个月用HPV16/31/35/39/45/58/59准病毒颗粒或棉尾兔乳头瘤病毒(CRPV)同时攻击动物。在免疫后6个月和12个月均观察到对所有HPV类型的强保护作用,包括在接受无佐剂疫苗的兔子中的强大保护作用。总之,当使用临床相关佐剂时,在其表面两个位点呈现HPV L2 17 - 36表位的AAVLP疫苗接种可诱导交叉中和血清抗体、生殖道针对HPV16的免疫以及针对7种最常见致癌性HPV类型皮肤攻击的长期保护。