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. 2020 Jun 30;8(3):348.
doi: 10.3390/vaccines8030348.

Duration of Cellular and Humoral Responses after Quadrivalent Human Papillomavirus Vaccination in Healthy Female Adults with or without Prior Type 16 and/or 18 Exposure

Lilin Lai  1 , Kevin Ault  2 , Nadine Rouphael  1 , Allison Beck  1 , Briyana Domjahn  1 , Yongxian Xu  1 , Evan J Anderson  3 , Andrew Cheng  1 , Aya Nakamura  4 , Rebecca J Hoagland  5 , Colleen Kelley  1 , Srilatha Edupuganti  1 , Karen Mask  1 , Mirjana Nesin  6 , Elizabeth R Unger  7 , Gitika Panicker  7 , Hagit David  6 , Mark J Mulligan  1   8
Affiliations

Duration of Cellular and Humoral Responses after Quadrivalent Human Papillomavirus Vaccination in Healthy Female Adults with or without Prior Type 16 and/or 18 Exposure

Lilin Lai et al. Vaccines (Basel). .

Abstract

Human papillomavirus virus (HPV) vaccines aim to provide durable protection and are ideal to study the association of cellular with humoral responses. We assessed the duration and characteristics of immune responses provided by the quadrivalent HPV (4vHPV) vaccine in healthy female adults with or without prior exposure with type 16 and 18 HPV. In a prospective cohort, vaccine naïve females received three doses of 4vHPV vaccine and were followed for two years to assess cellular (intracellular cytokine staining, proliferation and B cell ELISpot assays) and humoral (multiplex L1/L2 viral-like particles (VLP) and M4 ELISAs) responses. Frequencies of vaccine-specific CD4+ T cells correlated with antibody responses. Higher HPV antibody titers were found at all time points in participants previously exposed to HPV, except for anti-HPV-18 at Day 187 (one week post the third vaccination). Retrospective cohorts enrolled females who had previously received two or three 4vHPV doses and tested antibody titers by M4 ELISA and pseudovirion neutralization assay along with memory B cells (MBCs). Almost all women enrolled in a retrospective cohort with two prior doses and all women enrolled in a retrospective cohort with three prior doses had sustained antibody and memory responses. Our findings indicate that HPV vaccination induces a long-lasting, robust cellular and humoral immune responses.

Keywords: ELISA; HPV vaccine; T Cell responses; memory B cell responses; pseudovirion neutralization assay.

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Conflict of interest statement

E.J.A. has received research funding unrelated to this paper from Novavax, Micron, PaxVax, Pfizer, Merck, Sanofi-Pasteur, Regeneron, and Medimmune and has also consulted for AbbVie and Pfizer unrelated to this study. N.R. has received research funding unrelated to this paper from Sanofi-Pasteur, Pfizer, Quidel and Merck. All other authors, no conflicts.

Figures

Figure 1
Figure 1
Disposition of study subjects-consort flow diagram. n: the number of subjects.
Figure 2
Figure 2
Frequency and proportion of responders of HPV-specific CD4+ T cell induced by 4vHPV vaccination. (A) Frequency of HPV-16- (left panel) and HPV-18 (right panel)-specific CD4+ T cell response at Days 0, 67 and 187 in the prospective cohort for all (solid blue line), HPV-naïve (dashed red line) and HPV-exposed (dashed green line) subjects expressed as the number of total IFNγ, IL-2, IL-4 and IL-21 expressing cells per millions of total CD4 T cells; (B) proportion of responders for HPV-16- (left panel) and HPV-18 (right panel)-specific CD4+ T cell response at Days 67 and 187 in prospective cohort defined as subjects whose value was greater than the baseline value and with >180 HPV-16+ or >296 HPV-18+ CD4 T cells per million of total CD4 T cells for all (blue bar), HPV-naïve (red bar) and HPV-exposed (green bar) subjects.
Figure 3
Figure 3
Antibody levels measured by ELISA increased in response to HPV vaccination. HPV-16- (left side) specific and HPV-18-(right side) specific antibody (Ab) titers detected by ELISA (IU/mL) at Days 0, 67, 187, 365, 545 and 730 in prospective cohort for all (solid blue line), HPV-naïve (dashed red line) and HPV-exposed(dashed green line) subjects.
Figure 4
Figure 4
Antibody levels in retrospective cohort. (A) HPV-16- (left panel) and HPV-18-specific (right panel) ELISA Ab titers (IU/mL) and (B) pseudovirion neutralization titers in retrospective cohort with 2 or 3 doses of prior 4vHPV vaccination.
Figure 5
Figure 5
Frequency and proportion of MBC responders induced by 4vHPV. (A) Frequency of HPV-16- (left panel) and HPV-18-specific (right panel) specific memory B cells (MBCs) per millions of total IgG-secreting B cells at Days 0, 365, 545 and 730 in the prospective cohort for all (solid blue line), HPV-naïve (dashed red line) and HPV-exposed (dashed green line) subjects; (B) proportion of MBC responders (defined as subjects with >455 L-16 B cell or >450 L-18 B cell per millions of total IgG-secreting B cells) to HPV-16- (left panel) and HPV-18- (right panel) in the prospective cohort at Days 365, 454 and 730 as indicated at x-axis for all (blue bar), HPV-naïve (red bar) and HPV-exposed (green bar) subjects.
Figure 5
Figure 5
Frequency and proportion of MBC responders induced by 4vHPV. (A) Frequency of HPV-16- (left panel) and HPV-18-specific (right panel) specific memory B cells (MBCs) per millions of total IgG-secreting B cells at Days 0, 365, 545 and 730 in the prospective cohort for all (solid blue line), HPV-naïve (dashed red line) and HPV-exposed (dashed green line) subjects; (B) proportion of MBC responders (defined as subjects with >455 L-16 B cell or >450 L-18 B cell per millions of total IgG-secreting B cells) to HPV-16- (left panel) and HPV-18- (right panel) in the prospective cohort at Days 365, 454 and 730 as indicated at x-axis for all (blue bar), HPV-naïve (red bar) and HPV-exposed (green bar) subjects.
Figure 6
Figure 6
Frequency and proportion of MBC responders in retrospective cohorts. (A) Frequency of HPV-16- (left panel) and HPV-18-specific (right panel) specific memory B cells (MBCs) per millions of total IgG-secreting B cells. (B) Proportion of MBC responders to HPV-16- (left panel) and HPV-18- (right panel) defined as subjects with detectable (>455 cell/million of total IgG-secreting B cells) or L-18 (>450 cell/million of total IgG-secreting B cells) HPV type-specific memory B cells in retrospective cohort with 2 or 3 doses of prior 4vHPV vaccination.
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