TY - JOUR
T1 - Durable immunity to oncogenic human papillomaviruses elicited by adjuvanted recombinant Adeno-associated virus-like particle immunogen displaying L2 17-36 epitopes
AU - Jagu, Subhashini
AU - Karanam, Balusubramanyam
AU - Wang, Joshua W.
AU - Zayed, Hatem
AU - Weghofer, Margit
AU - Brendle, Sarah A.
AU - Balogh, Karla K.
AU - Tossi, Kerstin Pino
AU - Roden, Richard B.S.
AU - Christensen, Neil D.
N1 - Funding Information:
The study was funded by grants from Medigene AG to NDC and RBSR, and Public Health Service (grants.nih.gov) grants P50 CA098252 and CA118790 to RBSR.
Funding Information:
We have read the journal's policy and the authors of this manuscript have the following competing interests: The study was funded by grants from Medigene AG to Neil Christensen and Richard Roden. Richard Roden is an inventor of L2-related patents (US application 20090047301 Papillomavirus L2 N-Terminal Peptides for the Induction of Broadly Cross-Neutralizing Antibodies and US application 20130177585 PAPILLOMAVIRUS L2 N-TERMINAL PEPTIDES FOR THE INDUCTION OF BROADLY CROSS-NEUTRALIZING ANTIBODIES) licensed to Shantha Biotechnics Ltd., GlaxoSmithKline, PaxVax, Inc. and Acambis, Inc. Richard Roden and TC Wu are founders of Papivax LLC and scientific advisors to Papivax Biotech Inc. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict of interest policies. Kerstin Pino Tossi is an inventor of the AAV related patent application WO 2008/145400 “Mutated structural protein of a parvovirus” and related patent applications. Kerstin Pino Tossi, and Margit Weghofer are employees of Medigene AG. This does not alter our adherence to all the journal's policies on sharing data and materials.
Publisher Copyright:
© 2015.
PY - 2015/10/13
Y1 - 2015/10/13
N2 - 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.
AB - 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.
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U2 - 10.1016/j.vaccine.2015.09.005
DO - 10.1016/j.vaccine.2015.09.005
M3 - Article
C2 - 26382603
AN - SCOPUS:84943448583
SN - 0264-410X
VL - 33
SP - 5553
EP - 5563
JO - Vaccine
JF - Vaccine
IS - 42
ER -
