Cellular Immune Responses to Human Papillomavirus (HPV)–16 L1 in Healthy Volunteers Immunized with Recombinant HPV‐16 L1 Virus‐Like Particles

Pinto, Lígia A.; Edwards, J. L.; Castle, Philip E.; Harro, Clayton; Lowy, Douglas R.; Schiller, John T.; Wallace, Dora; Kopp, William C.; Adelsberger, Joseph W.; Baseler, Michael; Berzofsky, Jay A.; Hildesheim, Allan

doi:10.1086/376505

Cited by 158 publications

(119 citation statements)

References 32 publications

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“…Interestingly, there are also data that seem to demonstrate an active CMI response being activated from vaccination, but it is more controversial and less clear than the antibody response,13, 14, 15, 16 It is known that in benign disease such as RRP, there is normal full‐cycle replication of the virus, thus exposing the immune system (both humoral and CMI) to the full spectrum of viral antigens. In this regard, we postulated that an increased stimulation of the humoral arm via vaccination would also stimulate the CMI arm of the immune response to a certain degree via the mechanisms of cross‐presentation, thus yielding some therapeutic benefit against remaining infected cells that look clinically normal macroscopically.…”

Section: Discussionmentioning

confidence: 99%

Recurrent respiratory papillomatosis (RRP)–time for a reckoning?

Goon

Scholtz²,

Sudhoff³

2017

Laryngoscope Investig Oto

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ObjectivesRecurrent respiratory papillomatosis (RRP) is a rare disease, but one with severe morbidity and occasional mortality. The aetiological agent is human papillomavirus (HPV), and HPV types 6 and 11 account for over 90% of all cases. In the active phase of the disease, patients require multiple hospital admissions for surgical removal or ablation of these benign tumors, which are likely to obstruct the airways if left unchecked. Long‐term sequelae include scarring of the vocal cords, change in voice timbre, or even muteness if a tracheostomy is required. The aim of this study was to determine if adjuvant vaccination with the quadrivalent HPV L1 vaccine (Gardasil™) would decrease numbers of surgical treatments post‐vaccination.MethodsA prospective pilot study following a cohort of 12 RRP patients, all of whom gave fully informed consent to participate. All patients had their papillomas typed and if they were found to have types 6 or 11, were vaccinated at the time of first surgical treatment in the hospital, according to the manufacturer's protocols. Patients were followed up closely with 3 or 6 month follow‐up visits. Standard surgical treatments were given and were not affected by whether they participated in the study.ResultsWe found a >7‐fold decrease in the incidence rates of papillomatosis requiring surgical intervention from the pre‐vaccination period (47.44/1000 patient‐months) compared to the post‐vaccination period (6.71/1000 patient‐months).DiscussionSurgical treatments for RRP are robust markers for papillomata which require treatment because of the dangers of obstruction of the airway. Despite the small size of this cohort (due to the rarity of this disease), the data suggests that adjuvant use of quadrivalent HPV L1 vaccine imparts significant benefit to this group of patients. A large multi‐center randomized placebo controlled trial is required to definitively establish whether this hypothesis is true and can become the new standard of therapy.Level of Evidence3b

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Section: Discussionmentioning

confidence: 99%

Recurrent respiratory papillomatosis (RRP)–time for a reckoning?

Goon

Scholtz²,

Sudhoff³

2017

Laryngoscope Investig Oto

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“…A similar T-cell response was detected in adult female volunteers 18-25 years of age of whom PBMC were stimulated in vitro with L1-VLP. 50 Studies should be conducted to understand whether the presence of these preexistent vaccine-induced L1-specific T-cells may assist in establishing a conducive environment that allows a rapid induction and deployment of strong type 1 T-cell responses against the other HPV16 antigens at the time that the vaccinated virgin female subjects become sexually active and encounter a genuine HPV16 infection.…”

Section: Discussionmentioning

confidence: 99%

Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia

Poelgeest

Nijhuis

Kwappenberg

et al. 2005

Intl Journal of Cancer

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Cervical cancer is the possible outcome of a genital infection with high-risk human papillomavirus type 16 (HPV16) and is preceded by a phase of persistent HPV infection during which the host immune system fails to eliminate the virus. Our previous work showed that failure is reflected by the absence of type 1 T-cell immunity against HPV16 early antigens E2 and E6 in patients with HPV161 cervical lesions. We now show that a majority of both patients with cervical lesions and healthy subjects display HPV16 L1 peptide-specific type 1 T-cell responses with similar magnitude. The T-cell response in patients was directed at a broad range of peptides within L1, suggesting that during persistent or repeated exposure to HPV16 L1, the immune system maximizes its efforts to counter the viral challenge. Unlike the type 1 T-cell responses against HPV16 early antigens E2 and E6, type 1 T-cell immunity against L1 does not correlate with health or disease. This argues that T-cell responses against early and late HPV16 antigens essentially differ in the manner in which they are induced and regulated, as well as in their impact on the subsequent stages of HPV16-induced cervical disease. ' 2005 Wiley-Liss, Inc.Key words: HPV16; T cell; L1; VLP; cervical cancer; healthy individuals Infection of both men and women with oncogenic human papillomavirus (HPV) types, such as HPV type 16 (HPV16), is quite common 1-3 and leads to progressive disease in only a minor fraction of infected subjects. [4][5][6] The majority of the infections and HPV-induced epithelial lesions spontaneously resolve, most likely through intervention by the adaptive immune response. [7][8][9] In a majority of healthy subjects (approximately 60%) strong type 1 Tcell reactivity directed at the nonstructural proteins HPV16 E2 and E6 can be detected, [10][11][12] suggesting that these proteins are important target antigens for a protective immune response in humans, similar to what was found in animal models. [13][14][15] These animal models also revealed that L1-specific immunity can protect against infection with the cottontail rabbit papilloma virus 16 or the canine oral papilloma virus. [17][18][19] A large HPV16 L1-VLP vaccination trial in humans revealed that vaccine-induced immunity could prevent persistent HPV16 infections. 20 Although the immunologic evaluation of this trial was focused on the role of neutralizing antibodies in preventing viral infection, VLP vaccination must also have affected the underlying CD41 Th responses and possibly Th-dependent cell-mediated effector functions.Previous work has shown that patients diagnosed with HPV16 1 CIN display proliferative responses against HPV16 L1 21,22 and that there was no difference in such proliferative responses (measured by IL-2 production) between patients who cleared their lesions or in whom lesions persisted. 23 Immunity in such subjects may differ not so much in the quantitative aspects of the immune response but more in the quality of the response, as is indicated by our studies on immunity against...

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“…Immature DC were incubated in the presence or absence of HPV-16 VLP (10 lg/mL), or lipopolysaccharide (LPS, 2 lg/ mL; Sigma-Aldrich, St. Louis, MO) as a positive control for 24 h. The recombinant L1-VLP were expressed in a baculovirus system (Novavax, Rockville, MD) and produced for clinical usage as reported [39]. In neutralization assays, the antibodies were added 30 min before the addition of L1-VLP and incubated at 37 C. After incubation, cell-free supernatants were collected for cytokine analysis and cells were washed and analyzed by flow cytometry (FC500 Flow Cytometer; Beckman Coulter) for the expression of several surface markers (CD1a, CD3, CD14, CD11c, HLA class I, HLA class II, CD80, CD83, CD86, CD40 and appropriate isotype controls; all from Becton Dickinson, except CD3 and CD14 that were from Beckman Coulter).…”

Section: Activationmentioning

confidence: 99%

Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

et al. 2006

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Dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN), a specific C-type lectin expressed on DC, binds and transmits different pathogens to susceptible cells. In the present study, we examined the role of DC-SIGN in the capture of human papillomavirus (HPV) pseudovirions and activation of DC. We demonstrate that HPV virus-like particles (VLP) bind to DC-SIGN expressed on transfected Raji cells and that antibodies against DC-SIGN block this interaction. DC take up VLP, which activate expression of costimulatory markers and cytokines/ chemokines. Although our results indicate that DC-SIGN is not the major receptor for VLP in DC, this interaction contributes to the activation of DC surface antigens (HLA class I) and of various cytokines/chemokines, particularly TNF-a, IL-6, and RANTES. Induction of these markers in DC by VLP was significantly abrogated when binding to DC-SIGN was blocked by anti-DC-SIGN antibodies. These results suggest that DC-SIGN has a functional role in DC activation induced by HPV-16 L1-VLP, and thus highlight new aspects of DC interactions with HPV VLP. IntroductionThe C-type lectin dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN; CD209) is a pathogen recognition receptor that interacts with mannose residues of glycoproteins in a calciumdependent manner via its C-terminal carbohydrate recognition domain [1,2]. DC-SIGN acts both as an adhesion molecule and pathogen recognition receptor, facilitating DC binding and internalization of several viruses, including HIV-1 [3].In addition to HIV, DC-SIGN was recently shown to bind a variety of microorganisms such as CMV [4], Ebola virus [5], Dengue virus [6], hepatitis C virus [7,8], simian immunodeficiency virus [9], Leishmania [10], Candida albicans [11], Mycobacterium [12][13][14] and Schistosoma [15]. Some pathogens subvert DC functions to escape immune surveillance [16]. DC-SIGN is abundantly expressed primarily on DC, including those derived from monocytes and those located beneath the genital surface [3].Human papillomavirus (HPV) virus-like particles (VLP) are a promising vaccine candidate for HPV and cervical cancer [17][18][19][20]. Recent clinical trials have shown that VLP afford excellent protection against persistent infection [20,21]. Because of the lack of a suitable cell culture system for in vitro propagation of HPV and the unavailability of virions, HPV VLP have been used as soluble surrogates for native virus particles. The routes of HPV-16 L1-VLP entry in DC and the nature of cellular receptors involved in capture have been studied but remain to be fully characterized. HPV VLP Here, we report that HPV-16 L1-VLP particles bind to DC-SIGN in transfected cell lines, and to a lesser extent in DC, and that this interaction participates in L1-VLPinduced activation of DC. Thus, DC-SIGN is likely involved in DC activation by HPV VLP. Results and discussion HPV L1-VLP bind to DC-SIGN in DC-SIGN-transfected cell linesTo study interactions between L1-VLP and DC-SIGN, we...

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Cellular Immune Responses to Human Papillomavirus (HPV)–16 L1 in Healthy Volunteers Immunized with Recombinant HPV‐16 L1 Virus‐Like Particles

Cited by 158 publications

References 32 publications

Recurrent respiratory papillomatosis (RRP)–time for a reckoning?

Recurrent respiratory papillomatosis (RRP)–time for a reckoning?

Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia

Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

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