Systemic and mucosal immune responses to sublingual or intramuscular human papilloma virus antigens in healthy female volunteers

Zhiming Huo, Sara L Bissett, Raphaela Giemza, Simon Beddows, Clarissa Oeser, David J M Lewis, Zhiming Huo, Sara L Bissett, Raphaela Giemza, Simon Beddows, Clarissa Oeser, David J M Lewis

Abstract

The sublingual route has been proposed as a needle-free option to induce systemic and mucosal immune protection against viral infections. In a translational study of systemic and mucosal humoral immune responses to sublingual or systemically administered viral antigens, eighteen healthy female volunteers aged 19-31 years received three immunizations with a quadravalent Human Papilloma Virus vaccine at 0, 4 and 16 weeks as sublingual drops (SL, n = 12) or intramuscular injection (IM, n = 6). IM antigen delivery induced or boosted HPV-specific serum IgG and pseudovirus-neutralizing antibodies, HPV-specific cervical and vaginal IgG, and elicited circulating IgG and IgA antibody secreting cells. SL antigens induced ~38-fold lower serum and ~2-fold lower cervical/vaginal IgG than IM delivery, and induced or boosted serum virus neutralizing antibody in only 3/12 subjects. Neither route reproducibly induced HPV-specific mucosal IgA. Alternative delivery systems and adjuvants will be required to enhance and evaluate immune responses following sublingual immunization in humans.

Trial registration: ClinicalTrials.govNCT00949572.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CONSORT diagram.
Figure 1. CONSORT diagram.
Figure 2. Circulating antibody secreting cell responses.
Figure 2. Circulating antibody secreting cell responses.
The Y axis values indicate the group median frequency of antibody secreting cells (ASCs) per 105 PBMCs plated, secreting IgG (white bars) or IgA (hatched bars) against Gardasil vaccine or L1 HPV16. Panel A: subjects immunized intramuscularly. Panel B: subjects immunized sublingually. Arrows indicate immunizations. Box: 25th to 75th percentiles, whiskers: 10 to 90 percentiles.
Figure 3. Serum, cervical and vaginal IgG…
Figure 3. Serum, cervical and vaginal IgG responses.
The Y axis values (note different scales) indicate group mean anti-L1 HPV6 (circles), HPV16 (triangles) and HPV18 (squares) IgG concentration in serum (panel A), cervical secretions (panel B) or vaginal secretions (panel C), for subjects immunized intramuscularly (left, open symbols), or sublingually (right, closed symbols). Error bars SEM.
Figure 4. Cervical and vaginal IgA responses.
Figure 4. Cervical and vaginal IgA responses.
The Y axis values indicate group mean anti-L1 HPV6 (circles), HPV16 (triangles) and HPV18 (squares) IgG concentration in cervical secretions (panel A), or vaginal secretions (panel B), for subjects immunized intramuscularly (left, open symbols), or sublingually (right, closed symbols). Error bars SEM.

References

    1. Czerkinsky C, Cuburu N, Kweon MN, Anjuere F, Holmgren J. Sublingual vaccination. Hum Vaccin. 2011;7:110–114.
    1. Cho HJ, Kim JY, Lee Y, Kim JM, Kim YB, et al. Enhanced humoral and cellular immune responses after sublingual immunization against human papillomavirus 16 L1 protein with adjuvants. Vaccine. 2010;28:2598–2606.
    1. Cuburu N, Kweon MN, Hervouet C, Cha HR, Pang YY, et al. Sublingual immunization with nonreplicating antigens induces antibody-forming cells and cytotoxic T cells in the female genital tract mucosa and protects against genital papillomavirus infection. J Immunol. 2009;183:7851–7859.
    1. Cuburu N, Kweon MN, Song JH, Hervouet C, Luci C, et al. Sublingual immunization induces broad-based systemic and mucosal immune responses in mice. Vaccine. 2007;25:8598–8610.
    1. Hervouet C, Luci C, Cuburu N, Cremel M, Bekri S, et al. Sublingual immunization with an HIV subunit vaccine induces antibodies and cytotoxic T cells in the mouse female genital tract. Vaccine. 2010;28:5582–5590.
    1. Song JH, Nguyen HH, Cuburu N, Horimoto T, Ko SY, et al. Sublingual vaccination with influenza virus protects mice against lethal viral infection. Proc Natl Acad Sci U S A. 2008;105:1644–1649.
    1. Lewis DJ, Huo Z, Barnett S, Kromann I, Giemza R, et al. Transient facial nerve paralysis (Bell's palsy) following intranasal delivery of a genetically detoxified mutant of Escherichia coli heat labile toxin. PLoS One. 2009;4:e6999.
    1. Holmgren J, Adamsson J, Anjuere F, Clemens J, Czerkinsky C, et al. Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA. Immunol Lett. 2005;97:181–188.
    1. Frati F, Moingeon P, Marcucci F, Puccinelli P, Sensi L, et al. Mucosal immunization application to allergic disease: sublingual immunotherapy. Allergy Asthma Proc. 2007;28:35–39.
    1. Czerkinsky C, Holmgren J. Mucosal Delivery Routes for Optimal Immunization: Targeting Immunity to the Right Tissues. Curr Top Microbiol Immunol 2010
    1. Lewis DJ, Fraser CA, Mahmoud AN, Wiggins RC, Woodrow M, et al. Phase I Randomised Clinical Trial of an HIV-1(CN54), Clade C, Trimeric Envelope Vaccine Candidate Delivered Vaginally. PLoS One. 2011;6:e25165.
    1. Mills KH, Cosgrove C, McNeela EA, Sexton A, Giemza R, et al. Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a. Infect Immun. 2003;71:726–732.
    1. Pastrana DV, Buck CB, Pang YY, Thompson CD, Castle PE, et al. Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papillomavirus neutralization assay for HPV16 and HPV18. Virology. 2004;321:205–216.
    1. Draper E, Bissett SL, Howell-Jones R, Edwards D, Munslow G, et al. Neutralization of non-vaccine human papillomavirus pseudoviruses from the A7 and A9 species groups by bivalent HPV vaccine sera. Vaccine. 2011;29:8585–8590.
    1. Ferguson M, Wilkinson DE, Heath A, Matejtschuk P. The first international standard for antibodies to HPV 16. Vaccine. 2011;29:6520–6526.
    1. Lewis DJ, Novotny P, Dougan G, Griffin GE. The early cellular and humoral immune response to primary and booster oral immunization with cholera toxin B subunit. Eur J Immunol. 1991;21:2087–2094.
    1. Desai S, Chapman R, Jit M, Nichols T, Borrow R, et al. Prevalence of human papillomavirus antibodies in males and females in England. Sex Transm Dis. 2011;38:622–629.
    1. Jit M, Vyse A, Borrow R, Pebody R, Soldan K, et al. Prevalence of human papillomavirus antibodies in young female subjects in England. Br J Cancer. 2007;97:989–991.
    1. Brown DR, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16–26 years. J Infect Dis. 2009;199:926–935.
    1. Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler CM, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res (Phila) 2009;2:868–878.
    1. Paavonen J, Naud P, Salmeron J, Wheeler CM, Chow SN, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009;374:301–314.
    1. Schiller JT, Lowy DR. Vaccines to prevent infections by oncoviruses. Annu Rev Microbiol. 2010;64:23–41.
    1. Frazer I. Correlating immunity with protection for HPV infection. International Journal of Infectious Diseases. 2007;11:S10–S16.
    1. Moingeon P, Lombardi V, Saint-Lu N, Tourdot S, Bodo V, et al. Adjuvants and vector systems for allergy vaccines. Immunol Allergy Clin North Am. 2011;31:xii.
    1. Pomfret TC, Gagnon JM, Jr, Gilchrist AT. Quadrivalent human papillomavirus (HPV) vaccine: a review of safety, efficacy, and pharmacoeconomics. J Clin Pharm Ther. 2011;36:1–9.
    1. Clemens JD, Jertborn M, Sack D, Stanton B, Holmgren J, et al. Effect of neutralization of gastric acid on immune responses to an oral B subunit, killed whole-cell cholera vaccine. J Infect Dis. 1986;154:175–178.
    1. Levine MM, Hughes TP, Young CR, O'Donnell S, Craig JP, et al. Antigenicity of purified glutaraldehyde-treated cholera toxoid administered orally. Infect Immun. 1978;21:158–162.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe