Immunogenicity of a Plasmodium vivax vaccine based on the duffy binding protein formulated using adjuvants compatible for use in humans.

The invasion of reticulocytes by Plasmodium vivax merozoites is dependent on the interaction of the Plasmodium vivax Duffy Binding Protein (PvDBP) with the Duffy antigen receptor for chemokines (DARC). The N-terminal cysteine-rich region II of PvDBP (PvDBPII), which binds DARC, is a leading P. vivax malaria vaccine candidate. Here, we have evaluated the immunogenicity of recombinant PvDBPII formulated with the adjuvants Matrix-M and GLA-SE in mice. Analysis of the antibody responses revealed comparable ELISA recognition titres as well as similar recognition of native PvDBP in P. vivax schizonts by immunofluorescence assay. Moreover, antibodies elicited by the two adjuvant formulations had similar functional properties such as avidity, isotype profile and inhibition of PvDBPII-DARC binding. Furthermore, the anti-PvDBPII antibodies were able to block the interaction of DARC with the homologous PvDBPII SalI allele as well as the heterologous PvDBPII PvW1 allele from a Thai clinical isolate that is used for controlled human malaria infections (CHMI). The cross-reactivity of these antibodies with PvW1 suggest that immunization with the PvDBPII SalI strain should neutralize reticulocyte invasion by the challenge P. vivax strain PvW1.

Investigation of viral etiology in potentially malignant disorders and oral squamous cell carcinomas in non-smoking, non-drinking patients.

Head and neck squamous cell carcinomas (HNSCC) are the seventh most frequent cancers. Among HNSCCs, oral squamous cell carcinomas (OSCCs) include several anatomical locations of the oral cavity, but exclude the oropharynx. The known risk factors for OSCCs are mainly alcohol consumption and tobacco use for at least 75-80% of cases. In addition to these risk factors, Human papillomavirus (HPV) types 16 and 18, classified as high-risk (HR) HPV genotypes, are considered as risk factors for oropharyngeal cancers, but their role in the development of OSCC remains unclear. We tested the hypothesis of viral etiology in a series of 68 well-characterized OSCCs and 14 potentially malignant disorders (PMD) in non-smoking, non-drinking (NSND) patients using broad-range, sensitive molecular methodologies. Deep-sequencing of the transcriptome did not reveal any vertebrate virus sequences other than HPV transcripts, detected in only one case. In contrast, HPV DNA was detected in 41.2% (28/68) and 35.7% (5/14) of OSCC and PMD cases, respectively. Importantly, 90.9% (30/33) of these belonged to the Betapapillomavirus genus, but no viral transcripts were detected. Finally, high-throughput sequencing revealed reads corresponding to transcripts of the Trichomonas vaginalis virus (TVV), which were confirmed by RT-PCR in two OSCCs. Our results strongly suggest that Alphapapillomavirus genotypes classified as HR are not involved in the development of OSCCs in NSND patients and that known oncogenic infectious agents are absent in these specific OSCCs. Any possible direct or indirect role of Betapapillomavirus genus members and TVV in OSCCs remains speculative and requires further investigation.

Broad-Range Papillomavirus Transcriptome as a Biomarker of Papillomavirus-Associated Cervical High-Grade Cytology.

Human papillomaviruses (HPVs) are responsible for >99% of cervical cancers. Molecular diagnostic tests based on the detection of viral DNA or RNA have low positive predictive values for the identification of cancer or precancerous lesions. Triage with the Papanicolaou test lacks sensitivity; and even when combined with molecular detection of high-risk HPV, this results in a significant number of unnecessary colposcopies. We have developed a broad-range detection test of HPV transcripts to take a snapshot of the transcriptome of 16 high-risk or putative high-risk HPVs in cervical lesions (HPVs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82). The purpose of this novel molecular assay, named HPV RNA-Seq, is to detect and type HPV-positive samples and to determine a combination of HPV reads at certain specific viral spliced junctions that can better correlate with high-grade cytology, reflecting the presence of precancerous cells. In a proof-of-concept study conducted on 55 patients, starting from cervical smears, we have shown that HPV RNA-Seq can detect papillomaviruses with performances comparable to a widely used HPV reference molecular diagnostic kit; and a combination of the number of sequencing reads at specific early versus late HPV transcripts can be used as a marker of high-grade cytology, with encouraging diagnostic performances as a triage test.

Effectiveness of Human Papillomavirus Vaccination on Prevalence of Vaccine Genotypes in Young Sexually Active Women in France.

Background: Effectiveness of human papillomavirus (HPV) vaccines in the context of both guidelines, which recommend vaccination at 14 years and modest vaccine coverage, is poorly documented. Methods: Residual specimens from females aged <25 years undergoing chlamydia testing were collected, together with demographic, sexual behavior, and vaccine status data. Human pappilomavirus genotypes were determined using the PapilloCheck test system. We compared vaccine type (VT; types 6, 11, 16, 18) prevalence according to vaccination status and identified factors associated with VT prevalence. Results: Of 3736 eligible samples, 822 were from vaccinated women according to immunization record, 1021 from women self-reporting vaccination, and 1893 from unvaccinated women. Adjusted vaccine effectiveness for confirmed vaccinated compared with unvaccinated women was 95.93% (95% confidence interval [CI] = 90.22-98.32) against VT HPV and 38.37% (95% CI = 12.68-56.51) against cross-reactive genotypes (HPV 31, 33, 45), respectively. Vaccine type HPV prevalence was significantly lower (0.61%) among confirmed-vaccinated women than among those who self-reported vaccination or unvaccinated women (1.76% and 15.0%, respectively). Factors associated with prevalent VT in multivariable analysis were vaccine status, positive Chlamydia trachomatis and ≥4 partners in the preceding year. Conclusion: Our study demonstrates evidence of high effectiveness of HPV prophylactic vaccines at an individual level, supporting that wider implementation will help to reduce cervical cancer and precursors incidence.

Human papillomavirus types distribution in organised cervical cancer screening in France.

BACKGROUND: Knowledge of prevalence rates and distribution of human papillomavirus (HPV) genotypes prior high HPV vaccine coverage is necessary to assess its expected impact on HPV ecology and on cervical lesions and cancers. METHODS: Residual specimens of cervical cytology (N = 6,538) were obtained from 16 sites participating in organised cervical cancer screening pilot programs throughout France, anonymised and tested for HPV DNA using the PapilloCheck® genotyping test. Samples were stratified according to age of women and cytological grades. RESULTS: The age-standardised prevalence rates of HPV 16 and/or 18 (with or without other high-risk types) was 47.2% (95% Confidence Interval, CI: 42.4-52.1) in high-grade squamous intraepithelial lesions (HSILs), 20.2% in low-grade SIL (95% CI: 16.7-23.7) and 3.9% (95% CI: 2.8-5.1) in normal cytology. Overall HR HPV were detected in 13.7% (95%I CI: 11.7-15.6) of normal cytology. In women below 30 years of age, 64% of HSILs were associated with HPV16 and/or 18. In our study population, HPV16 was the most commonly detected type in all cervical grades with prevalence rates ranking from 3.0% in normal cytology to 50.9% in HSILs. HPV16 was also detected in 54% (27/50) of invasive cervical cancers including 5 adenocarcinomas. CONCLUSION: HPV16 was strongly associated with cervical precancer and cancer. The high prevalence rates of HPV16/18 infection among women below 30 years of age with HSILs suggests that the impact of vaccination would be primarily observed among young women.