Current Prophylactic Vaccines Research Articles

Cervical human papillomavirus genotypes in a high HIV setting: A scoping review of a decade of human papillomavirus epidemiological research in Botswana.

Cervical cancer burden is still high in low- and middle-income countries, including Botswana. Persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer. Accurate knowledge of HPV diversity associated to cervical cancer in sub-Saharan Africa may provide accurate understanding of the natural history of HPV infection in these contexts. The goal of this review was to consolidate existing evidence on cervical HPV infection and to conduct a pooled analysis of data from all eligible Botswana studies. After a successful review of twelve studies on cervical HPV genotypes that met the inclusion criteria, HPV-16 genotype was the most frequently discovered in women with pre-cancerous and cancer lesions, followed by HPV-18. HPV-16 in HIV-positive women with precancerous lesions to cancer is between 45% and 47.7%, and between 4.5% and 26.1% for HPV-18. With reference to other HPV genotypes, the proportion of HPV-35 and HPV-58 (13-16%) seems relatively consistent among the studies, however HPV-58 appears to be more common in HIV-positive subjects compared to HIV-negative women. Indeed, HPV-45 seems to be frequently detected in women with cervical cancer compared to women with precancerous lesions. Regarding the low-risk HPV genotypes, an appropriate breakdown has been provided. In conclusion, the current prophylactic vaccines against HPV-16 and HPV-18, which have demonstrated good immunogenicity in HIV-infected populations, may still prevent infection and ultimately cancer.

A broadly protective vaccine against cutaneous human papillomaviruses

Skin colonization by human papillomavirus (HPV) is typically related to inconspicuous cutaneous infections without major disease or complications in immunocompetent individuals. However, in immunosuppressed patients, especially organ transplanted recipients, cutaneous HPV infections may cause massive, highly spreading and recurrent skin lesions upon synergism with UV-exposure. Current HPV prophylactic vaccines are not effective against cutaneous HPV types (cHPV). By applying a modular polytope-based approach, in this work, we explored different vaccine candidates based on selected, tandemly arranged cHPV-L2 epitopes fused to thioredoxin (Trx) as a scaffold protein. Upon conversion to heptameric nanoparticles with the use of a genetically fused oligomerization domain, our candidate Trx-L2 vaccines induce broadly neutralizing immune responses against 19 cHPV in guinea pigs. Similar findings were obtained in mice, where protection against virus challenge was also achieved via passive transfer of immune sera. Remarkably, immunization with the candidate cHPV vaccines also induced immune responses against several mucosal low- and high-risk HPV types, including HPV16 and 18. Based on cumulative immunogenicity data but also on ease and yield of production, we identified a lead vaccine candidate bearing 12 different cHPV-L2 epitopes that holds great promise as a scalable and GMP production-compatible lead molecule for the prevention of post-transplantation skin lesions caused by cHPV infection.

Risk assessment for long- and short-range airborne transmission of SARS-CoV-2, indoors and outdoors.

Preventive measures to reduce infection are needed to combat the COVID-19 pandemic and prepare for a possible endemic phase. Current prophylactic vaccines are highly effective to prevent disease but lose their ability to reduce viral transmission as viral evolution leads to increasing immune escape. Long-term proactive public health policies must therefore complement vaccination with available nonpharmaceutical interventions aiming to reduce the viral transmission risk in public spaces. Here, we revisit the quantitative assessment of airborne transmission risk, considering asymptotic limits that considerably simplify its expression. We show that the aerosol transmission risk is the product of three factors: a biological factor that depends on the viral strain, a hydrodynamical factor defined as the ratio of concentration in viral particles between inhaled and exhaled air, and a face mask filtering factor. The short-range contribution to the risk, present both indoors and outdoors, is related to the turbulent dispersion of exhaled aerosols by air drafts and by convection (indoors), or by the wind (outdoors). We show experimentally that airborne droplets and CO2 molecules present the same dispersion. As a consequence, the dilution factor, and therefore the risk, can be measured quantitatively using the CO2 concentration, regardless of the room volume, the flow rate of fresh air, and the occupancy. We show that the dispersion cone leads to a concentration in viral particles, and therefore a short-range transmission risk, inversely proportional to the squared distance to an infected person and to the flow velocity. The aerosolization criterion derived as an intermediate result, which compares the Stokes relaxation time to the Lagrangian time-scale, may find application for a broad class of aerosol-borne pathogens and pollutants.

Effects of the Prophylactic HPV Vaccines on HPV Type Prevalence and Cervical Pathology.

Vaccination programs with the current prophylactic HPV vaccines started in most countries around 2008 with introduction of the bivalent Cervarix HPV16/18 vaccine, rapidly followed by Gardasil (HPV6/11/16/18) and, finally, Gardasil 9 (HPV6/11/16/18/31/33/45/52/58), from 2015. Many studies have now confirmed their ability to prevent infection with vaccine-covered HPV types, and the subsequent development of either genital warts and/or cervical neoplasia, although this is clearly more effective in younger women vaccinated prior to sexual debut. Most notably, reductions in the prevalence of vaccine-covered HPV types were also observed in unvaccinated women at the same geographical location, presumably by sexual dissemination of these changes, between vaccinated and unvaccinated women. Furthermore, there are several studies that have demonstrated vaccine-associated HPV type-replacement, where vaccine-covered, high-risk HPV types are replaced by high-risk HPV types not covered by the vaccines, and these changes were also observed in vaccinated and unvaccinated women in the same study population. In light of these observations, it is not entirely clear what effects vaccine-associated HPV type-replacement will have, particularly in older, unvaccinated women.

Potential Effects of Human Papillomavirus Type Substitution, Superinfection Exclusion and Latency on the Efficacy of the Current L1 Prophylactic Vaccines.

There are >200 different types of human papilloma virus (HPV) of which >51 infect genital epithelium, with ~14 of these classed as high-risk being more commonly associated with cervical cancer. During development of the disease, high-risk types have an increased tendency to develop a truncated non-replicative life cycle, whereas low-risk, non-cancer-associated HPV types are either asymptomatic or cause benign lesions completing their full replicative life cycle. HPVs can also be present as non-replicative so-called “latent” infections and they can also show superinfection exclusion, where cells with pre-existing infections with one type cannot be infected with a different HPV type. Thus, the HPV repertoire and replication status present in an individual can form a complex dynamic meta-community which changes with respect to both time and exposure to different HPV types. In light of these considerations, it is not clear how current prophylactic HPV vaccines will affect this system and the potential for iatrogenic outcomes is discussed in light of recent outcome data.

Current strategies against persistent human papillomavirus infection (Review).

Human papillomavirus (HPV) is the most common sexually transmitted infection, exhibiting a tropism for the epidermis and mucosae. The link between persistent HPV infection and malignancies involving the anogenital tract as well as the head and neck has been well‑established, and it is estimated that HPV‑related cancers involving various anatomical sites account for 4.5% of all human cancers. Current prophylactic vaccines against HPV have enabled the prevention of associated malignancies. However, the sizeable population base of current infection in whom prophylactic vaccines are not applicable, certain high‑risk HPV types not included in vaccines, and the vast susceptible population in developing countries who do not have access to the costly prophylactic vaccines, put forward an imperative need for effective therapies targeting persistent infection. In this article, the life cycle of HPV, the mechanisms facilitating HPV evasion of recognition and clearance by the host immune system, and the promising therapeutic strategies currently under investigation, particularly antiviral drugs and therapeutic vaccines, are reviewed.

Evaluation of the thermal stability and the protective efficacy of spray-dried HPV vaccine, Gardasil® 9

ABSTRACT High-risk human papillomavirus (HPV) types are responsible for nearly all cases of cervical cancers. Cervarix® and Gardasil® 9 are the current prophylactic vaccines available that protect against the majority of HPVs associated with cancer. Although these vaccines are highly effective, HPV vaccine implementation has been slow, particularly in low-and-middle income countries. Major barriers to the widespread availability of the HPV vaccines is its cost and the requirement for continuous refrigeration (2–8°C). Here, we used spray drying along with stabilizing excipients to formulate a thermostable Gardasil® 9 vaccine. We evaluated the immunogenicity and protective efficacy of the vaccine in mice immediately after spray drying and following storage for three months at 4°C, 25°C, and 40°C. The immunogenicity studies were performed using Gardasil® 9 as a whole antigen, and not individual HPV types, for ELISA. At the dose tested, the spray dried vaccine conferred protection against HPV following storage at temperatures up to 40°C. In addition to the spray-dried vaccine, our studies revealed that the Gardasil® 9 vaccine, as currently marketed, may be stored and transported at elevated temperatures for up to 3 months without losing efficacy, especially against HPV16. This study is critical, as a thermostable vaccine will decrease vaccine cost associated with cold-chain maintenance and could increase vaccine access and coverage, especially in remote regions of the world.

Neutralizing epitopes and intragenotypic variants of human papillomavirus 16 (HPV16)

Cervical cancer is the second most common cancer in women worldwide. It is clear that persistent infection of high-risk human papillomaviruses (HR-HPVs) is the main cause for this disease. Among the several HPV types associated with carcinoma, HPV-16 is the most prevalent type and present in about 50% of tumor specimens. The major capsid protein (L1) of HPV can self-assemble into virus-like particles (VLPs) with immunogenicity similar to infectious virions. Neutralizing epitopes are the structural basis of the current prophylactic HPV vaccines. The efficacy of HPV vaccines is critically dependent upon the integrity of type-specific neutralizing epitopes. Recently, considerable headway has been made in studying the epitopes of HPV16 based on neutralizing antibodies. Notably, more and more HPV16 variants have appeared along with increasing immune pressure. To study the phenotypic variations in HPV16 L1 protein, 1 204 naturally occurring sequences were analyzed and a phylogenetic tree was then constructed including four clades. Moreover, after compared the aforementioned sequences with the 114K reference sequence, eight hot mutation sites , six specialized mutation sites and 20 epitope-related mutation sites were found. Generally, sera raised against VLPs can neutralize the corresponding HPV types, but not other types. However, it is not known whether intragenotypic variants of human papillomavirus type 16 (HPV-16) can be neutralized by sera vaccinated with a single variant VLPs. It is, therefore, imperative to understand the neutralizing epitopes and intragenotypic variants of HPV-16 for the production of prophylactic vaccines with high potency and broad coverage. Key words: Human papillomavirus; Major capsid protein; Amino acid substitution; Neutralizing epitope; Variant

Evaluating the proposal of paediatric virology: An interview with Professor Tina Dalianis, Professor of Tumour Virology at Karolinska Institutet.

Professor Tina Dalianis, Professor of Tumour Virology at Karolinska Institutet in Stockholm, Sweden, is a well-known virologist with a strong international reputation and seminal contributions in tumour virology in the fields of human papillomaviruses (HPVs) and polyomaviruses. According to Professor Dalianis, over the past decades virology has significantly contributed to the understanding of many infectious diseases in medicine. In addition, quite a few antiviral therapies have been developed in recent years that have been very helpful, while the study of viruses has also provided valuable information about their host cells and basic cell biology. She highlights the association of HPVs with tonsillar and base of tongue cancers, as well as their epidemic rise. She also refers to additional biomarkers, which are under investigation, in order to better individualise patient care, by for example, de-escalating or targeted therapy, whenever this is possible. She clarifies that the current prophylactic vaccines against HPVs are very efficient for the types they are directed against and she hopes that boys will also soon be vaccinated against HPVs, particularly in countries where there is a low percentage of girls being vaccinated. According to Professor Dalianis, the knowledge of virology is very useful in general paediatric practice; the proposal of paediatric virology as a medical subspecialty is absolutely correct and it would be very useful, as there is much to be done. In the context of the ‘4th Workshop on Paediatric Virology’, Professor Tina Dalianis will give the plenary lecture of this scientific event and will focus on changes in the prevalence of different HPVs in genital and oral samples in some groups of youth in Sweden during the introduction of the vaccines against HPVs.

TLR8 combined withTLR3 or TLR4 agonists enhances DC-NK driven effector Tc1 cells

BackgroundMost current prophylactic vaccines confer protection primarily through humoral immunity. Indeed, aluminum salts which have been widely used as adjuvants in vaccines primarily enhance Th2-driven antibody responses. Therefore, new vaccines formulation is moving toward a careful selection of adjuvants that also elicit significant Th1 or Tc1 responses. Several TLR agonists have been tested as potential new adjuvants in clinical and preclinical studies with some efficacy. These studies suggest that combining more than one of TLR ligands enhances the magnitude of immune responses to cancer and infectious disease. ObjectivesIn order to evaluate the synergistic effect of TLR agonists for effective induction of cellular immunity, we investigated the effects of single and/or combined TLR agonists on monocyte-derived DC maturation, DC-NK crosstalk and ultimately naïve T cells polarization into effector T cells. ResultsAmong the adjuvants tested, we found that TLR3, TLR4, TLR7/8 and TLR8 agonists were the most effective adjuvants to increase the expression levels of antigen-presenting, co-stimulatory molecules and production of cytokines by maturing DCs. When combined, TLR3+8 and TLR4+8 synergistically optimized DC maturation and IFN-γ secretion from NK cells co-cultured with DCs. Interestingly, co-culture of DC-NK-T treated with aluminum salt produced the highest percentage of effector memory CFSE-CCR7- Th1 cells whereas TLR3+8 and TLR4+8 treated co-cultures produced the highest percentage of effector memory CFSE-CCR7- Tc1 cells producing IFN-γ. Finally, while both TLR3+8 or TLR4+8 treated co-cultures generated similar frequency of Th1 and Tc1 effector cells, the effector cells from the latter co-culture produced quantitatively more IFN-γ in the supernatant. ConclusionOur data indicate that if in need of an enhanced DC-NK mediated cellular immunity one may select TLR agonists with defined synergistic effects.

TLR8/7 combined withTLR3 or TLR4 enhances DC-NK driven effector T cells

Abstract Background Most current prophylactic vaccines confer protection primarily through humoral immunity. Indeed, aluminum salts that have been used extensively as adjuvants primarily enhance Th2-driven antibody responses. Therefore, new vaccines formulation is moving toward a careful selection of adjuvants that also elicit significant Th1 responses or CTLs. Various TLR ligands have been tested as potential adjuvants in clinical and preclinical studies with some efficacy. These studies suggest that combining more than one of TLR ligands enhance the magnitude of immune responses to cancer and infectious disease. In order to evaluate the synergic effect of TLR agonists for effective induction of cellular immunity, we investigated the effects of individual and/or combined TLR agonists on monocyte-derived DC maturation, DC-NK cross talk and ultimately T cells differentiation. Results Among the TLR agonists tested, we found TLR8/7 in combination with TLR3 or TLR4 synergistically optimize DC maturation and IFN-γ secretion from NK cells co-cultured with DCs. Moreover, co-culture of DC-NK-T treated with TLR8/7 and TLR3 or TLR4 increased the frequency of IFN-γ producing effector T cells when compared to Aluminum salt-treated cultures. Conclusions Our data suggests that enhancement of a desired cellular immunity requires a selection of TLR agonists with defined synergistic effects. NIH-NIAID 1R03AI103750-01A1

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Prophylactic vaccines against high risk HPV has become important because of the high oncogenic potential of the virus and its association with cervical cancer development, one of the most common and fatal cancers among women worldwide. The objective of this article is describe the state of the art of the current prophylactic and therapeutic HPV vaccines, analyzing their characteristics, advantages, disadvantages and scientific reports on its use and safety in the population. A systematic revision of the latest advances in the development of prophylactic and therapeutic vaccines against HPV was performed. Prophylactic vaccination is effective and essential for the prevention of uterine cervical cancer; new therapeutic vaccines have been shown at the initial phases to be promising contributing in the regression of premalignant or malignant in situ lesions.

Capsid display of a conserved human papillomavirus L2 peptide in the adenovirus 5 hexon protein: a candidate prophylactic hpv vaccine approach.

BackgroundInfection by any one of 15 high risk human papillomavirus (hrHPV) types causes most invasive cervical cancers. Their oncogenic genome is encapsidated by L1 (major) and L2 (minor) coat proteins. Current HPV prophylactic vaccines are composed of L1 virus-like particles (VLP) that elicit type restricted immunity. An N-terminal region of L2 protein identified by neutralizing monoclonal antibodies comprises a protective epitope conserved among HPV types, but it is weakly immunogenic compared to L1 VLP. The major antigenic capsid protein of adenovirus type 5 (Ad5) is hexon which contains 9 hypervariable regions (HVRs) that form the immunodominant neutralizing epitopes. Insertion of weakly antigenic foreign B cell epitopes into these HVRs has shown promise in eliciting robust neutralizing antibody responses. Thus here we sought to generate a broadly protective prophylactic HPV vaccine candidate by inserting a conserved protective L2 epitope into the Ad5 hexon protein for VLP-like display.MethodsFour recombinant adenoviruses were generated without significant compromise of viral replication by introduction of HPV16 amino acids L2 12–41 into Ad5 hexon, either by insertion into, or substitution of, either hexon HVR1 or HVR5.ResultsVaccination of mice three times with each of these L2-recombinant adenoviruses induced similarly robust adenovirus-specific serum antibody but weak titers against L2. These L2-specific responses were enhanced by vaccination in the presence of alum and monophoryl lipid A adjuvant. Sera obtained after the third immunization exhibited low neutralizing antibody titers against HPV16 and HPV73. L2-recombinant adenovirus vaccination without adjuvant provided partial protection of mice against HPV16 challenge to either the vagina or skin. In contrast, vaccination with each L2-recombinant adenovirus formulated in adjuvant provided robust protection against vaginal challenge with HPV16, but not against HPV56.ConclusionWe conclude that introduction of HPV16 L2 12–41 epitope into Ad5 hexon HVR1 or HVR5 is a feasible method of generating a protective HPV vaccine, but further optimization is required to strengthen the L2-specific response and broaden protection to the more diverse hrHPV.

Distribution of HPV Genotype in Invasive Cervical Carcinoma and Cervical Intraepithelial Neoplasia in Zhejiang Province, Southeast China: Establishing the Baseline for Surveillance.

Human papillomavirus (HPV) are firmly established as the principal causative agent for cervical carcinoma. Current vaccines may provide some protection for women from cervical carcinoma linked to HPV genotype 16 and 18. This may be the best vaccine for Western women, but the geographical variation in HPV distributions may not make it the most appropriate vaccine for China or Asia. This study provided an observational, retrospective, hospital-based cross-sectional study on the distribution of HPV genotypes among 5410 women with invasive cervical cancer (ICC) or cervical intraepithelial neoplasia (CIN). Overall, the positive rates of the four HPV types included in current prophylactic vaccines were counted, the two high-risk types (HPV-16 and -18) covered by current vaccines represented 66.9% of women with squamous cancer, 55.0% with adenocarcinoma, 64.9% with adenosquamous carcinoma and 77.4% of other type ICC, as well as 59.5% of CIN III, 45.0% of CIN II and 38.1% of CIN I cases. As expected, two low-risk types (HPV-6 and -11) included in the quadrivalent vaccine did not show good coverage data. Particularly worth mentioning is the fact that the addition of HPV-52 and -58 to the vaccine cocktail would increase cancer protection in our population, potentially preventing up to beyond 16% of squamous/adenosquamous carcinoma and other type of cervical cancers, and 7.75% of adenocarcinomas. It might also potentially reduce the rate of CIN III by a further 28.6% and CIN II and I by a third. This study established the baseline for surveillance in Zhejiang Province, and provides data for further vaccine designs: a quadrivalent HPV vaccine covering HPV-16/-58/-18/-52, would be more welcome in our region in the forthcoming year compared to the currently available vaccine.

Current and future prophylactic vaccines for hepatitis C virus

The development of a vaccine is necessary to combat the global hepatitis C virus (HCV) epidemic. The key to the development of a prophylactic vaccine is understanding the immune response in those who spontaneously resolve HCV infections versus those who develop chronic disease. Several promising vaccine candidates based on the use of viral vectors are currently in Phase I and Phase II clinical trials. The recently solved structures of the E2 glycoprotein have greatly aided epitope- and antibody-based vaccine design.

Costs and cost-effectiveness of 9-valent human papillomavirus (HPV) vaccination in two East African countries.

BackgroundCurrent prophylactic vaccines against human papillomavirus (HPV) target two of the most oncogenic types, HPV-16 and -18, which contribute to roughly 70% of cervical cancers worldwide. Second-generation HPV vaccines include a 9-valent vaccine, which targets five additional oncogenic HPV types (i.e., 31, 33, 45, 52, and 58) that contribute to another 15–30% of cervical cancer cases. The objective of this study was to determine a range of vaccine costs for which the 9-valent vaccine would be cost-effective in comparison to the current vaccines in two less developed countries (i.e., Kenya and Uganda).Methods and FindingsThe analysis was performed using a natural history disease simulation model of HPV and cervical cancer. The mathematical model simulates individual women from an early age and tracks health events and resource use as they transition through clinically-relevant health states over their lifetime. Epidemiological data on HPV prevalence and cancer incidence were used to adapt the model to Kenya and Uganda. Health benefit, or effectiveness, from HPV vaccination was measured in terms of life expectancy, and costs were measured in international dollars (I$). The incremental cost of the 9-valent vaccine included the added cost of the vaccine counterbalanced by costs averted from additional cancer cases prevented. All future costs and health benefits were discounted at an annual rate of 3% in the base case analysis. We conducted sensitivity analyses to investigate how infection with multiple HPV types, unidentifiable HPV types in cancer cases, and cross-protection against non-vaccine types could affect the potential cost range of the 9-valent vaccine. In the base case analysis in Kenya, we found that vaccination with the 9-valent vaccine was very cost-effective (i.e., had an incremental cost-effectiveness ratio below per-capita GDP), compared to the current vaccines provided the added cost of the 9-valent vaccine did not exceed I$9.7 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$5.2 and I$16.2 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP where the 9-valent vaccine would be considered cost-effective, the thresholds of added costs associated with the 9-valent vaccine were I$27.3, I$14.5 and I$45.3 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. In Uganda, vaccination with the 9-valent vaccine was very cost-effective when the added cost of the 9-valent vaccine did not exceed I$8.3 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$4.5 and I$13.7 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP, the thresholds of added costs associated with the 9-valent vaccine were I$23.4, I$12.6 and I$38.4 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively.ConclusionsThis study provides a threshold range of incremental costs associated with the 9-valent HPV vaccine that would make it a cost-effective intervention in comparison to currently available HPV vaccines in Kenya and Uganda. These prices represent a 71% and 61% increase over the price offered to the GAVI Alliance ($5 per dose) for the currently available 2- and 4-valent vaccines in Kenya and Uganda, respectively. Despite evidence of cost-effectiveness, critical challenges around affordability and feasibility of HPV vaccination and other competing needs in low-resource settings such as Kenya and Uganda remain.

Cervical cancers associated with human papillomavirus types 16, 18 and 45 are diagnosed in younger women than cancers associated with other types: A cross-sectional observational study in Wales and Scotland (UK)

BackgroundMost cervical cancers are attributable to infection with one of fourteen types of human papillomavirus (HPV), but HPV types differ in oncogenic potential. Characterisation of cancers associated with specific HPV types is required to predict the likely impact of current prophylactic vaccines and the potential benefits of vaccine formulations including additional HPV types. ObjectiveThe study aimed to correlate HPV type with histology and age at diagnosis, in Invasive Cervical Cancers (ICCs) from two of the devolved countries of the UK (Wales and Scotland). Study designCentralised histopathology review and rigorously standardised HPV-DNA typing were applied to 592 ICC diagnosed 2001–2006. HPV status was analysed in relation to histology and age at diagnosis. ResultsHPV infection was confirmed in 535/592 cases. Among the 497 tumours infected with single HPV types, the three most common types were HPV16 (62% 95%CI: 57.6–66.1), HPV18 (18.9% 95%CI: 15.7–22.6) and HPV45 (5.4% 95%CI: 3.7–7.8). HPV16 or 18 were present in 80.9% of HPV positive cases. Women with tumours associated with HPV types 16, 18 and 45 were on average 10.5 years younger at diagnosis than women with tumours associated with other HPV types. ConclusionsProphylactic vaccines targeting HPV16 and 18 could potentially prevent up to 80.9% of ICC in the populations investigated. Cancers associated with HPV16, 18 and 45 were diagnosed at younger ages, supporting the hypothesis of faster progression than for tumours caused by other HPV types.

Patterns of Human Papillomavirus Types in Multiple Infections: An Analysis in Women and Men of the High Throughput Human Papillomavirus Monitoring Study

BackgroundTo evaluate the pattern of co-infection of human papillomavirus (HPV) types in both sexes in Sweden.MethodsCell samples from genital swabs, first-void urine, and genital swabs immersed in first-void urine were collected in the present cross-sectional High Throughput HPV Monitoring study. Overall, 31,717 samples from women and 9,949 from men (mean age 25) were tested for 16 HPV types using mass spectrometry. Multilevel logistic regression was used to estimate the expected number of multiple infections with specific HPV types, adjusted for age, type of sample, and accounting for correlations between HPV types due to unobserved risk factors using sample-level random effects. Bonferroni correction was used to allow for multiple comparisons (120).ResultsObserved-to-expected ratio for any multiple infections was slightly above unity in both sexes, but, for most 2-type combinations, there was no evidence of significant departure from expected numbers. HPV6/18 was found more often and HPV51/68 and 6/68 less often than expected. However, HPV68 tended to be generally underrepresented in co-infections, suggesting a sub-optimal performance of our testing method for this HPV type.ConclusionsWe found no evidence for positive or negative clustering between HPV types included in the current prophylactic vaccines and other untargeted oncogenic types, in either sex.

Potential Benefits of Second-Generation Human Papillomavirus Vaccines

BackgroundCurrent prophylactic vaccines against human papillomavirus (HPV) target two oncogenic types (16 and 18) that contribute to 70% of cervical cancer cases worldwide. Our objective was to quantify the range of additional benefits conferred by second-generation HPV prophylactic vaccines that are expected to expand protection to five additional oncogenic types (31, 33, 45, 52 and 58).MethodsA microsimulation model of HPV and cervical cancer calibrated to epidemiological data from two countries (Kenya and Uganda) was used to estimate reductions in lifetime risk of cervical cancer from the second-generation HPV vaccines. We explored the independent and joint impact of uncertain factors (i.e., distribution of HPV types, co-infection with multiple HPV types, and unidentifiable HPV types in cancer) and vaccine properties (i.e., cross-protection against non-targeted HPV types), compared against currently-available vaccines.ResultsAssuming complete uptake of the second-generation vaccine, reductions in lifetime cancer risk were 86.3% in Kenya and 91.8% in Uganda, representing an absolute increase in cervical cancer reduction of 26.1% in Kenya and 17.9% in Uganda, compared with complete uptake of current vaccines. The range of added benefits was 19.6% to 29.1% in Kenya and 14.0% to 19.5% in Uganda, depending on assumptions of cancers attributable to multiple HPV infections and unidentifiable HPV types. These effects were blunted in both countries when assuming vaccine cross-protection with both the current and second-generation vaccines.ConclusionSecond-generation HPV vaccines that protect against additional oncogenic HPV types have the potential to improve cervical cancer prevention. Co-infection with multiple HPV infections and unidentifiable HPV types can influence vaccine effectiveness, but the magnitude of effect may be moderated by vaccine cross-protective effects. These benefits must be weighed against the cost of the vaccines in future analyses.

Vaccine Strategies against Human Papillomavirus: A Discussion Focused on Developing Countries

Cervical cancer is the second most common form of cancer among women, and responsible for 274,000 deaths each year, most of which occur in developing countries. Persistent infection with high-risk human papillomavirus (HR-HPV) is an essential factor in the development of cervical cancer and also a contributory factor in other types of cancer. The current prophylactic HPV vaccines provide protection against the -16 and -18 genotypes which are most commonly associated with cervical cancer worldwide. However, the increased costs of these vaccines inhibit their implementation in developing countries, affecting their viability. Moreover, a therapeutic vaccine is needed for women who are already infected by HPV and/or affected by HPV-related cancer. A number of innovative approaches to combat and treat HPV infection are currently being studied and some of these will be consider in this work, together with the development of new vaccines, especially in seriously affected areas located in developing countries. At the same time, there will be a discussion of the issues involved in carrying out effective HPV vaccination programs; these will take account of financial constraints, the lack of adequate infrastructure and the competing priorities, that are found in the surrounding social context of the developing countries.