The humoral response to Gardasil over four years as defined by Total IgG and competitive Luminex immunoassay

Brown, Darron R.; Garland, Suzanne M.; Ferris, Daron G.; Joura, Elmar A.; Steben, Marc; James, Margaret K.; Radley, David; Vuocolo, Scott; Garner, Elizabeth; Haupt, Richard M.; Bryan, Janine T.

doi:10.4161/hv.7.2.13948

Cited by 96 publications

(88 citation statements)

References 37 publications

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“…This finding was expected, as the anti-HPV18 antibody used in the cLIA has been optimized for its specificity against a neutralizing epitope through displacing a monoclonal antibody directed at a single neutralizing epitope for each HPV type (15). The IgG LIA, however, measures a wider antibody profile than that of the cLIA (13). If that highly specific neutralizing epitope used by cLIA happens to be highly immunodominant, then antibody responses are long lasting in the cLIA, like those seen in anti-HPV16.…”

Section: Discussionmentioning

confidence: 83%

“…Samples are tested at a 1:100 and a 1:10,000 dilution. To each well, the VLP-microspheres for types 6, 11, 16, 18, Following the second incubation period, the plates are washed 3 times, and the samples are analyzed on a Bio-Plex (Luminex) instrument (13).…”

Section: Laboratory Methods (I) Multiplexed Competitive Luminex Immumentioning

confidence: 99%

“…A more pronounced decline in HPV18 titers was observed, as measured by cLIA, with a month 48 seropositivity rate of 65%. However, when the same serum samples were tested in the total IgG Luminex immunoassay (LIA), a pseudovirion neutralization assay that measures all IgG antibodies produced in response to vaccination, data showed that total HPV18 seropositivity was approximately 97% at month 48 (13).…”

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confidence: 99%

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Evaluation of the Long-Term Anti-Human Papillomavirus 6 (HPV6), 11, 16, and 18 Immune Responses Generated by the Quadrivalent HPV Vaccine

Nygård

Saah

Munk

et al. 2015

Clin Vaccine Immunol

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This quadrivalent human papillomavirus (qHPV) (HPV6, -11, -16, and -18) vaccine long-term follow-up (LTFU) study is an ongoing extension of a pivotal clinical study (FUTURE II) taking place in the Nordic region. The LTFU study was designed to evaluate the effectiveness, immunogenicity, and safety of the qHPV vaccine (Gardasil) for at least 10 years following completion of the base study. The current report presents immunogenicity data from testing samples of the year 5 LTFU visit (approximately 9 years after vaccination). FUTURE II vaccination arm subjects, who consented to being followed in the LTFU, donated serum at regular intervals and in 2012. Anti-HPV6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA), and in addition, serum samples from 2012 were analyzed by the total IgG Luminex immunoassay (LIA) (n ‫؍‬ 1,598). cLIA geometric mean titers (GMTs) remained between 70% and 93% of their month 48 value depending on HPV type. For all HPV types, the lower bound of the 95% confidence interval (CI) for the year 9 GMTs remained above the serostatus cutoff value. The proportion of subjects who remained seropositive based on the IgG LIA was higher than the proportion based on cLIA, especially for anti-HPV18. As expected, the anti-HPV serum IgG and cLIA responses were strongly correlated for all HPV types. Anti-HPV GMTs and the proportion of vaccinated individuals who are seropositive remain high for up to 9 years of follow-up after vaccination.

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Section: Discussionmentioning

confidence: 83%

Section: Laboratory Methods (I) Multiplexed Competitive Luminex Immumentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation of the Long-Term Anti-Human Papillomavirus 6 (HPV6), 11, 16, and 18 Immune Responses Generated by the Quadrivalent HPV Vaccine

Nygård

Saah

Munk

et al. 2015

Clin Vaccine Immunol

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“…A striking illustration of this phenomenon was the finding that one-third of Gardasil vaccinees had become HPV18 seronegative by cLIA about 5 years after vaccination, while they remained completely protected against HPV18-related lesions (19). Interestingly, 97% of the vaccinees turned out to be HPV18 seropositive when tested for total HPV18 VLP-specific IgGs (4). Even in vitro pseudovirion (PsV) neutralization assays (28), which currently are considered the gold standard, may be of insufficient sensitivity to provide a correlate with breakthrough infection, since their analytic sensitivity is similar to that of the direct ELISAs (11,12).…”

mentioning

confidence: 96%

A Murine Genital-Challenge Model Is a Sensitive Measure of Protective Antibodies against Human Papillomavirus Infection

Longet

Schiller

Bobst

et al. 2011

J Virol

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The available virus-like particle (VLP)-based prophylactic vaccines against specific human papillomavirus (HPV) types afford close to 100% protection against the type-associated lesions and disease. Based on papillomavirus animal models, it is likely that protection against genital lesions in humans is mediated by HPV type-restricted neutralizing antibodies that transudate or exudate at the sites of genital infection. However, a correlate of protection was not established in the clinical trials because few disease cases occurred, and true incident infection could not be reliably distinguished from the emergence or reactivation of prevalent infection. In addition, the current assays for measuring vaccine-induced antibodies, even the gold standard HPV pseudovirion (PsV) in vitro neutralization assay, may not be sensitive enough to measure the minimum level of antibodies needed for protection. Here, we characterize the recently developed model of genital challenge with HPV PsV and determine the minimal amounts of VLP-induced neutralizing antibodies that can afford protection from genital infection in vivo after transfer into recipient mice. Our data show that serum antibody levels >100-fold lower than those detectable by in vitro PsV neutralization assays are sufficient to confer protection against an HPV PsV genital infection in this model. The results clearly demonstrate that, remarkably, the in vivo assay is substantially more sensitive than in vitro PsV neutralization and thus may be better suited for studies to establish correlates of protection.Cervical cancer, the second most common cause of cancer death in women worldwide, is associated with high-risk types of human papillomavirus (HPV) infections (27). HPV vaccines based on L1 virus-like particles (VLPs) have been shown to be safe and efficient at preventing infections and precancerous lesions caused by HPV vaccine-related types (26, 33) and now have been commercialized, specifically the HPV6/11/16/18 VLP Gardasil and the HPV16/18 VLP Cervarix vaccines. Neutralizing antibodies (Ab) are thought to be the primary immune mechanism of protection by HPV vaccination, primarily based on preclinical papillomavirus (PV) animal models showing that the passive transfer of immunized sera is protective in naïve rabbits and dogs against skin and oral mucosal challenge, respectively (3, 31). In addition, clinical trials showed that vaccinated individuals developed robust anti-VLP antibody titers in serum (15, 32) and in cervicovaginal secretions (21, 23), and that antibody-mediated cross-type neutralization in in vitro assays largely parallels the cross-type protection in the trials. However, these trials did not allow the establishment of antibody concentrations or thresholds that could be correlated to protection, mainly because too few disease cases occurred (26, 33) and because breakthrough infections could not be unambiguously distinguished from the emergence or reactivation of prevalent infection. In addition, the serological assays that were used in the trials (pr...

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“…Several VLP products have been evaluated in clinical trials. In addition to a hepatitis B virus VLP-based licensed vaccine, two human papillomavirus (HPV) VLP vaccines were recently licensed in the United States (6,9,15,38).…”

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confidence: 99%

H5N1 Virus-Like Particle Vaccine Elicits Cross-Reactive Neutralizing Antibodies That Preferentially Bind to the Oligomeric Form of Influenza Virus Hemagglutinin in Humans

Khurana

Verma

et al. 2011

J Virol

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The humoral response to Gardasil over four years as defined by Total IgG and competitive Luminex immunoassay

Cited by 96 publications

References 37 publications

Evaluation of the Long-Term Anti-Human Papillomavirus 6 (HPV6), 11, 16, and 18 Immune Responses Generated by the Quadrivalent HPV Vaccine

Evaluation of the Long-Term Anti-Human Papillomavirus 6 (HPV6), 11, 16, and 18 Immune Responses Generated by the Quadrivalent HPV Vaccine

A Murine Genital-Challenge Model Is a Sensitive Measure of Protective Antibodies against Human Papillomavirus Infection

H5N1 Virus-Like Particle Vaccine Elicits Cross-Reactive Neutralizing Antibodies That Preferentially Bind to the Oligomeric Form of Influenza Virus Hemagglutinin in Humans

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