Concomitant human papillomavirus (HPV) vaccination and screening for elimination of HPV and cervical cancer.

HPV vaccination with concomitant HPV-based screening of young women has been proposed for faster cervical cancer elimination. We describe the baseline results of a population-based trial of this strategy to reduce the incidence of HPV. All 89,547 women born 1994-1999 and resident in the capital region of Sweden were personally invited to concomitant HPV vaccination and HPV screening with 26,125 women (29.2%) enrolled between 2021-05-03 and 2022-12-31. Baseline HPV genotyping of cervical samples from the study participants finds, compared to pre-vaccination prevalences, a strong decline of HPV16 and 18 in birth cohorts previously offered vaccination, some decline for cross-protected HPV types but no decline for HPV types not targeted by vaccines. Our dynamic transmission modelling predicts that the trial could reduce the incidence of high-risk HPV infections among the 1994-1998 cohorts by 62-64% in 3 years. Baseline results are prevalences of HPV infection, validated transmission model projections, and power estimates for evaluating HPV incidence reductions at follow-up (+/-0.1% with 99.9% confidence). In conclusion, concomitant HPV vaccination and HPV screening appears to be a realistic option for faster cervical cancer elimination. Clinicaltrials.gov identifier: NCT04910802; EudraCT number: 2020-001169-34.

[Research progress on the differences between T and B cell responses to three different forms of human papilloma virus (HPV) vaccination].

One of the most prevalent malignancies in women is cervical cancer. Cervical cancer is mostly brought on by chronic high-risk human papillomavirus 16 (HPV16) and HPV18 infection. Currently, the widely used HPV vaccines are the bivalent Cervarix, the tetravalent Gardasil, and the 9-valent Gardasil-9.There are differences in T cell effector molecule changes, B cell antibody level, duration, age and the injection after vaccination of the three vaccines.

Reduced risk of CIN2+ recurrence in women immunized with a 9-valent HPV vaccine post-excision: Retrospective cohort study.

The main aim of our study was to investigate the specific contribution of a 9-valent human papillomavirus vaccine (9vHPV) to the recurrence risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women vaccinated post-excision. Therefore, we conducted a retrospective monocentric cohort study in women aged 22-49 years undergoing conization between 2014 and 2023. The 9vHPV-vaccinated women were matched to unvaccinated women for age and follow-up duration in a 1:2 ratio to eliminate allocation bias. The risk of CIN2+ recurrence was estimated by the incidence rate ratio using Poisson regression with adjustment for comorbidities, smoking status, nulliparity, CIN grade, positive cone margin, and HPV genotypes. The CIN2+ recurrence rates in 147 women enrolled in the analysis were 18 and 2 cases per 100,000 person-days for unvaccinated and vaccinated women, respectively, during a mean follow-up period of 30 months (±22 months). A reduction in CIN2+ recurrences by 90% (95% confidence interval: 12-99%) was documented in 9vHPV-vaccinated participants compared to women undergoing only surgical excision. Moreover, vaccinated women with a positive cone margin showed a 42% (though non-significant) reduction in relapse (p = .661). Full post-conization vaccination with the 9vHPV contributed to an additional reduction in the risk of CIN2+ recurrence. This finding is consistent with current knowledge and suggests a high adjuvant effect of the 9vHPV vaccine.

Assessing the reduction of viral infectivity in HPV16/18-positive women after one, two, and three doses of Gardasil-9 (RIFT): Study protocol.

Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706.

Monitoring HPV Prevalence and Risk Cofactors for Abnormal Cytology in the Post-Vaccination Period among Croatian Women.

The incidence and mortality rate of cervical cancer in Croatia remains a health challenge despite screening efforts. Besides the persistent infection with HPV, the development of cancer is also associated with some cofactors. The goal of this study was to assess circulating HPV genotypes and risk factors for the development of cervical precancer after almost 16 years from the onset of HPV vaccination in Croatia. In this study, a total of 321 women attending gynecological care were evaluated. Relevant medical and demographic information, including cytology, were collected. HPV genotyping was performed by PCR. Comparing the HPV types found in circulation in the pre-vaccination (1999-2015) and post-vaccination periods (2020-2023), a statistically significant reduction in HPV 31 was noted, while the overall prevalence increased in the post-vaccination period. Besides the expected HPV positivity as a risk factor, the history of smoking was associated with LSIL or worse cytology at enrollment. For the first time, this population study revealed a statistically significant shift in the HPV genotype in the post-vaccination period, as well as the confirmation of risk factors for the development of abnormal cytology among Croatian women.

Immunogenicity of quadrivalent human papillomavirus vaccine among Alaska Native children aged 9-14 years at 5 years after vaccination.

BACKGROUND: Persistent human papillomavirus (HPV) infection can cause anogenital and oropharyngeal cancers. Many HPV infections and HPV-associated cancers are vaccine-preventable. Studies suggest long-term persistence of vaccine-induced antibodies. However, data are limited among Alaska Native people. METHODS: During 2011-2014, we enrolled Alaska Native children aged 9-14 years who received a 3-dose series of quadrivalent HPV vaccine (4vHPV). We collected sera at 1 month and 1, 2, 3, and 5 years post-vaccination to evaluate trends in type-specific immunoglobulin G antibody concentrations for the 4vHPV types (HPV 6/11/16/18). RESULTS: All participants (N = 469) had detectable antibodies against all 4vHPV types at all timepoints post-vaccination. For all 4vHPV types, antibody levels peaked by 1 month post-vaccination and gradually declined in subsequent years. At 5 years post-vaccination, antibody levels were higher among children who received 4vHPV at a younger age. CONCLUSIONS: Alaska Native children maintained antibodies against all 4vHPV types at 5 years post-vaccination.

Accelerate vaccine development using seamless phase 2/3 trial designs.

BACKGROUND: Traditional vaccine development, often a lengthy and costly process of three separated phases. However, the swift development of COVID-19 vaccines highlighted the critical importance of accelerating the approval of vaccines. This article showcases a seamless phase 2/3 trial design to expedite the development process, particularly for multi-valent vaccines. RESEARCH DESIGN AND METHODS: This study utilizes simulation to compare the performance of seamless phase 2/3 design with that of conventional trial design, specifically by re-envisioning a 9-valent HPV vaccine trial. Across three cases, several key performance metrics are evaluated: overall power, type I error rate, average sample size, trial duration, the percentage of early stop, and the accuracy of dose selection. RESULTS: On average, when the experimental vaccine was assumed to be effective, the seamless design that performed interim analyses based solely on efficacy saved 555.73 subjects, shortened trials by 10.29 months, and increased power by 3.70%. When the experimental vaccine was less effective than control, it saved an average of 887.73 subjects while maintaining the type I error rate below 0.025. CONCLUSION: The seamless design proves to be a compelling strategy for vaccine development, given its versatility in early stopping, re-estimating sample sizes, and shortening trial durations.

Human papillomavirus infection: Epidemiology, biology, host interactions, cancer development, prevention, and therapeutics.

Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. It is caused by the HPV, a DNA virus that infects epithelial cells in various mucous membranes and skin surfaces. HPV can be categorised into high-risk and low-risk types based on their association with the development of certain cancers. High-risk HPV types, such as HPV-16 and HPV-18, are known to be oncogenic and are strongly associated with the development of cervical, anal, vaginal, vulvar, penile, and oropharyngeal cancers. These types of HPV can persist in the body for an extended period and, in some cases, lead to the formation of precancerous lesions that may progress to cancer if left untreated. Low-risk HPV types, such as HPV-6 and HPV-11, are not typically associated with cancer but can cause benign conditions like genital warts. Genital warts are characterised by the growth of small, cauliflower-like bumps on the genital and anal areas. Although not life-threatening, they can cause discomfort and psychological distress. HPV is primarily transmitted through sexual contact, including vaginal, anal, and oral sex. It can also be transmitted through non-penetrative sexual activities that involve skin-to-skin contact. In addition to sexual transmission, vertical transmission from mother to child during childbirth is possible but relatively rare. Prevention of HPV infection includes vaccination and safe sexual practices. HPV vaccines, such as Gardasil and Cervarix, are highly effective in preventing infection with the most common high-risk HPV types. These vaccines are typically administered to adolescents and young adults before they become sexually active. Safe sexual practices, such as consistent and correct condom use and limiting the number of sexual partners, can also reduce the risk of HPV transmission. Diagnosis of HPV infection can be challenging because the infection is often asymptomatic, especially in men. In women, HPV testing can be done through cervical screening programs, which involve the collection of cervical cells for analysis. Abnormal results may lead to further diagnostic procedures, such as colposcopy or biopsy, to detect precancerous or cancerous changes. Overall, HPV infection is a prevalent sexually transmitted infection with significant implications for public health. Vaccination, regular screening, and early treatment of precancerous lesions are key strategies to reduce the burden of HPV-related diseases and their associated complications. Education and awareness about HPV and its prevention are crucial in promoting optimal sexual health. This study aimed to carry out a literature review considering several aspects involving HPV infection: Global distribution, prevalence, biology, host interactions, cancer development, prevention, therapeutics, coinfection with other viruses, coinfection with bacteria, association with head and neck squamous cell carcinomas, and association with anal cancer.

Precision and correlation of ED50 and endpoint titer method in measuring HPV vaccine immunogenicity.

Cervical cancer, the second leading cause of cancer-related deaths among women, is caused by human papillomavirus (HPV), a sexually transmitted virus. Vaccination is an effective preventive measure against viral infections and subsequent development of cervical cancer. Enzyme-linked immunosorbent assay (ELISA) is commonly used to measure specific binding antibody titers and assess the immunogenicity of test vaccines in preclinical models or clinical volunteers. Two methods of deriving titers, the endpoint titer (ET) and the effective dilution producing a median maximal effective fold of dilution (ED50) with a cut-off value, are widely used. For HPV, a pseudovirion-based neutralization assay (PBNA) is used to measure functional antibody titers. The ELISA binding titers and functional PBNA titers were found to be well-correlated for all nine HPV types tested in the vaccine, consistent with previous studies on HPV 16/18. Comparing the PBNA results with the two titration methods, the ED50 method showed higher precision and a closer correlation with PBNA results, both for individual types and pooled data analysis for all nine types. When comparing the titration results of the ET method based on a cut-off value with the ED50 method using all the data points across the dilution series, the ED50 method demonstrated better precision and a stronger correlation with PBNA results.

Cobertura da vacinação contra papilomavírus humano no Nordeste do Brasil, 2013-2021: estudo descritivo / Human papillomavirus vaccination coverage in Northeast Brazil, 2013-2021: a descriptive study / Cobertura de vacunación contra el virus del papiloma humano en el Nordeste de Brasil, 2013-2021: un estudio descriptivo

Objetivo: descrever a cobertura da vacina contra papilomavírus humano (HPV) na região Nordeste do Brasil, no período de 2013 a 2021. Métodos: estudo descritivo conduzido com dados obtidos do Programa Nacional de Imunizações, que estabelece a meta de 80% para a vacina contra o HPV para meninas entre 9 e 14 anos e meninos entre 11 e 14 anos. Resultados: as coberturas para as meninas foram de 73,9%, na primeira, e de 54,3% na segunda dose, e para meninos, as coberturas de cada dose foram de 49,7% e 32,6%, respectivamente; excetuando-se Ceará e Paraíba, que alcançaram coberturas acima de 80% na primeira dose para as meninas, nenhum estado alcançou a meta para as duas doses. Conclusões: entre 2013 e 2021, as coberturas da vacina contra HPV estiveram abaixo da meta para ambos os sexos, com exceção de Ceará e Paraíba, que atingiram a meta para a primeira dose no grupo de meninas.

Objective: to describe human papillomavirus (HPV) vaccination coverage in the Northeast region of Brazil, in the period from 2013 to 2021. Methods: this was a descriptive study conducted with data obtained from the National Immunization Program, which sets a goal of 80% coverage of HPV vaccination in girls aged between 9 and 14 years and boys aged between 11 and 14 years. Results: HPV vaccination coverage in girls was 73.9%, regarding the first dose, and 54.3% regarding the second dose, and for boys, the coverage of each dose was 49.7% and 32.6%, respectively; with the exception of the states of Ceará and Paraíba, which reached coverage above 80% regarding the first dose in girls, none of the states reached the goal for both doses. Conclusions: between 2013 and 2021, HPV vaccination coverage was below the target for both sexes, with the exception of the states of Ceará and Paraíba, which reached the goal for the first dose in the girls.

Objetivo: describir las coberturas de la vacuna contra el papilomavirus humano en la Región Nordeste de Brasil y sus estados, de 2013 a 2021. Métodos: se trata de un estudio descriptivo realizado con datos de cobertura vacunal obtenidos del Programa Nacional de Immunizaciones, que establece la meta del 80% para la vacuna. Los datos de población se obtuvieron del Departamento de Informática del Ministerio de Salud. Resultados: la cobertura de vacunación en niñas fue del 73,9% en la primera y del 54,3% en la segunda dosis; en niños la cobertura de cada dosis fue del 49,7% y 32,6%; Ceará y Paraíba alcanzaron una cobertura superior al 80% para la primera dosis en niñas, y ningún estado alcanzó la meta para las dos dosis. Conclusiones: la cobertura de la vacuna está por debajo de la meta para ambos sexos, con excepción de la primera dosis en niñas en Ceará y Paraíba.

RG2-VLP: a Vaccine Designed to Broadly Protect against Anogenital and Skin Human Papillomaviruses Causing Human Cancer.

The family of human papillomaviruses (HPV) includes over 400 genotypes. Genus α genotypes generally infect the anogenital mucosa, and a subset of these HPV are a necessary, but not sufficient, cause of cervical cancer. Of the 13 high-risk (HR) and 11 intermediate-risk (IR) HPV associated with cervical cancer, genotypes 16 and 18 cause 50% and 20% of cases, respectively, whereas HPV16 dominates in other anogenital and oropharyngeal cancers. A plethora of ßHPVs are associated with cutaneous squamous cell carcinoma (CSCC), especially in sun-exposed skin sites of epidermodysplasia verruciformis (EV), AIDS, and immunosuppressed patients. Licensed L1 virus-like particle (VLP) vaccines, such as Gardasil 9, target a subset of αHPV but no ßHPV. To comprehensively target both α- and ßHPVs, we developed a two-component VLP vaccine, RG2-VLP, in which L2 protective epitopes derived from a conserved αHPV epitope (amino acids 17 to 36 of HPV16 L2) and a consensus ßHPV sequence in the same region are displayed within the DE loop of HPV16 and HPV18 L1 VLP, respectively. Unlike vaccination with Gardasil 9, vaccination of wild-type and EV model mice (Tmc6Δ/Δ or Tmc8Δ/Δ) with RG2-VLP induced robust L2-specific antibody titers and protected against ß-type HPV5. RG2-VLP protected rabbits against 17 αHPV, including those not covered by Gardasil 9. HPV16- and HPV18-specific neutralizing antibody responses were similar between RG2-VLP- and Gardasil 9-vaccinated animals. However, only transfer of RG2-VLP antiserum effectively protected naive mice from challenge with all ßHPVs tested. Taken together, these observations suggest RG2-VLP's potential as a broad-spectrum vaccine to prevent αHPV-driven anogenital, oropharyngeal, and ßHPV-associated cutaneous cancers. IMPORTANCE Licensed preventive HPV vaccines are composed of VLPs derived by expression of major capsid protein L1. They confer protection generally restricted to infection by the αHPVs targeted by the up-to-9-valent vaccine, and their associated anogenital cancers and genital warts, but do not target ßHPV that are associated with CSCC in EV and immunocompromised patients. We describe the development of a two-antigen vaccine protective in animal models against known oncogenic αHPVs as well as diverse ßHPVs by incorporation into HPV16 and HPV18 L1 VLP of 20-amino-acid conserved protective epitopes derived from minor capsid protein L2.

Population-Based Incidence of Guillain-Barré Syndrome During Mass Immunization With Viral Vaccines: A Pooled Analysis.

Misunderstanding temporal coincidence of adverse events during mass vaccination and invalid assessment of possible safety concerns have negative effects on immunization programs, leading to low immunization coverage. We conducted this systematic review and meta-analysis to identify the incidence rates of GBS that are temporally associated with viral vaccine administration but might not be attributable to the vaccines. By literature search in Embase and PubMed, we included 48 publications and 2,110,441,600 participants. The pooled incidence rate of GBS was 3.09 per million persons (95% confidence interval [CI]: 2.67 to 3.51) within six weeks of vaccination, equally 2.47 per 100,000 person-year (95%CI: 2.14 to 2.81). Subgroup analyses illustrated that the pooled rates were 2.77 per million persons (95%CI: 2.47 to 3.07) for individuals who received the influenza vaccine and 2.44 per million persons (95%CI: 0.97 to 3.91) for human papillomavirus (HPV) vaccines, respectively. Our findings evidence the GBS-associated safety of virus vaccines. We present a reference for the evaluation of post-vaccination GBS rates in mass immunization campaigns, including the SARS-CoV-2 vaccine.

Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials.

In 2014 and 2021, two nucleic-acid vaccine candidates named MAV E2 and VGX-3100 completed phase III clinical trials in Mexico and U.S., respectively, for patients with human papillomavirus (HPV)-related, high-grade squamous intraepithelial lesions (HSIL). These well-tolerated but still unlicensed vaccines encode distinct HPV antigens (E2 versus E6+E7) to elicit cell-mediated immune responses; their clinical efficacy, as measured by HSIL regression or cure, was modest when compared with placebo or surgery (conization), but both proved highly effective in clearing HPV infection, which should help further optimize strategies for enhancing vaccine immunogenicity, toward an ultimate goal of preventing malignancies in millions of patients who are living with persistent, oncogenic HPV infection but are not expected to benefit from current, prophylactic vaccines. The major roadblocks to a highly efficacious and practical product remain challenging and can be classified into five categories: (i) getting the vaccines into the right cells for efficient expression and presentation of HPV antigens (fusion proteins or epitopes); (ii) having adequate coverage of oncogenic HPV types, beyond the current focus on HPV-16 and -18; (iii) directing immune protection to various epithelial niches, especially anogenital mucosa and upper aerodigestive tract where HPV-transformed cells wreak havoc; (iv) establishing the time window and vaccination regimen, including dosage, interval and even combination therapy, for achieving maximum efficacy; and (v) validating therapeutic efficacy in patients with poor prognosis because of advanced, recurrent or non-resectable malignancies. Overall, the room for improvements is still large enough that continuing efforts for research and development will very likely extend into the next decade.

Potential effectiveness of a therapeutic HPV intervention campaign in Uganda.

Cervical cancer is a major source of morbidity and mortality in Uganda. In addition to prophylactic HPV vaccination, secondary prevention strategies are needed to reduce cancer burden. We evaluated the potential cancer reductions associated with a hypothetical single-contact therapeutic HPV intervention-with 70% coverage and variable efficacy [30%-100%]-using a three-stage HPV modeling framework reflecting HPV and cervical cancer burden in Uganda. In the reference case, we assumed prophylactic preadolescent HPV vaccination starting in 2020 with 70% coverage. A one-time therapeutic intervention targeting 35-year-old women in 2025 (not age-eligible for prophylactic vaccination) averted 1801 cervical cancers per 100 000 women over their lifetime (100% efficacy) or 533 cancers per 100 000 (30% efficacy). Benefits were considerably smaller in birth cohorts eligible for prophylactic HPV vaccination (768 cases averted per 100 000 at 100% efficacy). Evaluating the population-level impact over 40 years, we found introduction of a therapeutic intervention in 2025 with 100% efficacy targeted annually to 30-year-old women averted 139 000 incident cervical cancers in Uganda. This benefit was greatly reduced if efficacy was lower (30% efficacy; 41 000 cases averted), introduction was delayed (2040 introduction; 72 000 cases averted) or both (22 000 cases averted). We demonstrate the potential benefits of a single-contact HPV therapeutic intervention in a low-income setting, but show the importance of high therapeutic efficacy and early introduction timing relative to existing prophylactic programs. Reduced benefits from a less efficacious intervention may be somewhat offset if available within a shorter time frame.

Switching clinic-based cervical cancer screening programs to human papillomavirus self-sampling: A cost-effectiveness analysis of vaccinated and unvaccinated Norwegian women.

Several countries have implemented primary human papillomavirus (HPV) testing for cervical cancer screening. HPV testing enables home-based, self-collected sampling (self-sampling), which provides similar diagnostic accuracy as clinician-collected samples. We evaluated the impact and cost-effectiveness of switching an entire organized screening program to primary HPV self-sampling among cohorts of HPV vaccinated and unvaccinated Norwegian women. We conducted a model-based analysis to project long-term health and economic outcomes for birth cohorts with different HPV vaccine exposure, that is, preadolescent vaccination (2000- and 2008-cohorts), multiage cohort vaccination (1991-cohort) or no vaccination (1985-cohort). We compared the cost-effectiveness of switching current guidelines with clinician-collected HPV testing to HPV self-sampling for these cohorts and considered an additional 44 strategies involving either HPV self-sampling or clinician-collected HPV testing at different screening frequencies for the 2000- and 2008-cohorts. Given Norwegian benchmarks for cost-effectiveness, we considered a strategy with an additional cost per quality-adjusted life-year below $55 000 as cost-effective. HPV self-sampling strategies considerably reduced screening costs (ie, by 24%-40% across cohorts and alternative strategies) and were more cost-effective than clinician-collected HPV testing. For cohorts offered preadolescent vaccination, cost-effective strategies involved HPV self-sampling three times (2000-cohort) and twice (2008-cohort) per lifetime. In conclusion, we found that switching from clinician-collected to self-collected HPV testing in cervical screening may be cost-effective among both highly vaccinated and unvaccinated cohorts of Norwegian women.

Engineering for an HPV 9-valent vaccine candidate using genomic constitutive over-expression and low lipopolysaccharide levels in Escherichia coli cells.

BACKGROUND: The various advantages associated with the growth properties of Escherichia coli have justified their use in the production of genetically engineered vaccines. However, endotoxin contamination, plasmid vector instability, and the requirement for antibiotic supplementation are frequent bottlenecks in the successful production of recombinant proteins that are safe for industrial-scaled applications. To overcome these drawbacks, we focused on interrupting the expression of several key genes involved in the synthesis of lipopolysaccharide (LPS), an endotoxin frequently responsible for toxicity in recombinant proteins, to eliminate endotoxin contamination and produce better recombinant proteins with E. coli. RESULTS: Of 8 potential target genes associated with LPS synthesis, we successfully constructed 7 LPS biosynthesis-defective recombinant strains to reduce the production of LPS. The endotoxin residue in the protein products from these modified E. coli strains were about two orders of magnitude lower than that produced by the wild-type strain. Further, we found that 6 loci-lpxM, lpxP, lpxL, eptA, gutQ and kdsD-were suitable for chromosomal integrated expression of HPV L1 protein. We found that a single copy of the expression cassette conferred stable expression during long-term antibiotic-free cultivation as compared with the more variable protein production from plasmid-based expression. In large-scale fermentation, we found that recombinant strains bearing 3 to 5 copies of the expression cassette had 1.5- to 2-fold higher overall expression along with lower endotoxin levels as compared with the parental ER2566 strain. Finally, we engineered and constructed 9 recombinant E. coli strains for the later production of an HPV 9-valent capsid protein with desirable purity, VLP morphology, and antigenicity. CONCLUSIONS: Reengineering the LPS synthesis loci in the E. coli ER2566 strain through chromosomal integration of expression cassettes has potential uses for the production of a 9-valent HPV vaccine candidate, with markedly reduced residual endotoxin levels. Our results offer a new strategy for recombinant E. coli strain construction, engineering, and the development of suitable recombinant protein drugs.

Special Issue "HPV in the Head and Neck Region".

Previously, human papillomaviruses were best known for causing diseases in the genital tract, where high-risk types may cause, e.g., cancer of the cervix uteri, while low risk types could cause condylomas [...].