TY - JOUR
T1 - Vaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity
AU - Karanam, Balasubramanyam
AU - Gambhira, Ratish
AU - Peng, Shiwen
AU - Jagu, Subhashini
AU - Kim, Dae Jin
AU - Ketner, Gary W.
AU - Stern, Peter L.
AU - Adams, Robert J.
AU - Roden, Richard B.S.
N1 - Funding Information:
The authors gratefully acknowledge Xenova Ltd, UK and CR UK for providing the TA-CIN, and Hawaii Biotech for the GPI-0100, and Saveria Campo (University of Glasgow, Scotland) for critical reading of this manuscript. We also thank John Schiller and Doug Lowy (NCI, NIH) for reagents and sera of patients vaccinated with HPV16 L1 VLP, Martin Műller (DKFZ, Germany) for codon-modified HPV16 L1 and L2, Tadahito Kanda (National Institute of Infectious Diseases, Japan) for codon-modified HPV31, and HPV58 L1 and L2. This research was supported by grants to RBSR from the PHS (National Cancer Institute, SPORE in Cervical Cancer, P50 CA098252 and CA118790) and the Mary Kay Ash Foundation. Finally, we apologize to the many investigators whose pertinent work could not be cited herein due to space constraints.
Funding Information:
Conflict of interest statement: RBSR is a paid consultant of Merck & Co, and Knobbe, Martens, Olson and Bear LLC. SJ and RBSR have received grant funding from GSK. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.
PY - 2009/2/11
Y1 - 2009/2/11
N2 - A vaccine comprising human papillomavirus type 16 (HPV16) L2, E6 and E7 in a single tandem fusion protein (termed TA-CIN) has the potential advantages of both broad cross-protection against HPV transmission through induction of L2 antibodies able to cross neutralize different HPV types and of therapy by stimulating T cell responses targeting HPV16 early proteins. However, patients vaccinated with TA-CIN alone develop weak HPV neutralizing antibody and E6/E7-specific T cell responses. Here we test TA-CIN formulated along with the adjuvant GPI-0100, a semi-synthetic quillaja saponin analog that was developed to promote both humoral and cellular immune responses. Subcutaneous administration to mice of TA-CIN (20 μg) with 50 μg GPI-0100, three times at biweekly intervals, elicited high titer HPV16 neutralizing serum antibody, robust neutralizing titers for other HPV16-related types, including HPV31 and HPV58, and neutralized to a lesser extent other genital mucosatropic papillomaviruses like HPV18, HPV45, HPV6 and HPV11. Notably, vaccination with TA-CIN in GPI-0100 protected mice from cutaneous HPV16 challenge as effectively as HPV16 L1 VLP without adjuvant. Formulation of TA-CIN with GPI-0100 enhanced the production of E7-specific, interferon γ producing CD8+ T cell precursors by 20-fold. Vaccination with TA-CIN in GPI-0100 also completely prevented tumor growth after challenge with 5 × 104 HPV16-transformed TC-1 tumor cells, whereas vaccination with TA-CIN alone delayed tumor growth. Furthermore, three monthly vaccinations with 125 μg of TA-CIN and 1000 μg GPI-0100 were well tolerated by pigtail macaques and induced both HPV16 E6/E7-specific T cell responses and serum antibodies that neutralized all HPV types tested.
AB - A vaccine comprising human papillomavirus type 16 (HPV16) L2, E6 and E7 in a single tandem fusion protein (termed TA-CIN) has the potential advantages of both broad cross-protection against HPV transmission through induction of L2 antibodies able to cross neutralize different HPV types and of therapy by stimulating T cell responses targeting HPV16 early proteins. However, patients vaccinated with TA-CIN alone develop weak HPV neutralizing antibody and E6/E7-specific T cell responses. Here we test TA-CIN formulated along with the adjuvant GPI-0100, a semi-synthetic quillaja saponin analog that was developed to promote both humoral and cellular immune responses. Subcutaneous administration to mice of TA-CIN (20 μg) with 50 μg GPI-0100, three times at biweekly intervals, elicited high titer HPV16 neutralizing serum antibody, robust neutralizing titers for other HPV16-related types, including HPV31 and HPV58, and neutralized to a lesser extent other genital mucosatropic papillomaviruses like HPV18, HPV45, HPV6 and HPV11. Notably, vaccination with TA-CIN in GPI-0100 protected mice from cutaneous HPV16 challenge as effectively as HPV16 L1 VLP without adjuvant. Formulation of TA-CIN with GPI-0100 enhanced the production of E7-specific, interferon γ producing CD8+ T cell precursors by 20-fold. Vaccination with TA-CIN in GPI-0100 also completely prevented tumor growth after challenge with 5 × 104 HPV16-transformed TC-1 tumor cells, whereas vaccination with TA-CIN alone delayed tumor growth. Furthermore, three monthly vaccinations with 125 μg of TA-CIN and 1000 μg GPI-0100 were well tolerated by pigtail macaques and induced both HPV16 E6/E7-specific T cell responses and serum antibodies that neutralized all HPV types tested.
KW - GPI-0100
KW - Human papillomavirus
KW - Vaccine
UR - http://www.scopus.com/inward/record.url?scp=58549113969&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58549113969&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2008.11.099
DO - 10.1016/j.vaccine.2008.11.099
M3 - Article
C2 - 19095032
AN - SCOPUS:58549113969
SN - 0264-410X
VL - 27
SP - 1040
EP - 1049
JO - Vaccine
JF - Vaccine
IS - 7
ER -