Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection.

Human Papillomavirus (HPV) type variants have been classified into lineages and sublineages based upon their whole genome sequence. Here we have examined the specificity of antibodies generated following natural infection with lineage variants of oncogenic types (HPV16, 18, 31, 33, 45, 52 and 58) by testing serum samples assembled from existing archives from women residing in Africa, The Americas, Asia or Europe against representative lineage-specific pseudoviruses for each genotype. We have subjected the resulting neutralizing antibody data to antigenic clustering methods and created relational antigenic profiles for each genotype to inform the delineation of lineage-specific serotypes. For most genotypes, there was evidence of differential recognition of lineage-specific antigens and in some cases of a sufficient magnitude to suggest that some lineages should be considered antigenically distinct within their respective genotypes. These data provide compelling evidence for a degree of lineage specificity within the humoral immune response following natural infection with oncogenic HPV.

A virus-like particle-based bivalent PCSK9 vaccine lowers LDL-cholesterol levels in non-human primates.

Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of LDL-C metabolism, have emerged as promising approaches for reducing elevated LDL-C levels. Here, we evaluated the cholesterol-lowering efficacy of virus-like particle (VLP) based vaccines that target epitopes found within the LDL receptor (LDL-R) binding domain of PCSK9. In both mice and non-human primates, a bivalent VLP vaccine targeting two distinct epitopes on PCSK9 elicited strong and durable antibody responses and lowered cholesterol levels. In macaques, a VLP vaccine targeting a single PCSK9 epitope was only effective at lowering LDL-C levels in combination with statins, whereas immunization with the bivalent vaccine lowered LDL-C without requiring statin co-administration. These data highlight the efficacy of an alternative, vaccine-based approach for lowering LDL-C.

A Virus-like particle-based bivalent PCSK9 vaccine lowers LDL-cholesterol levels in Non-Human Primates.

Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of LDL-C metabolism, have emerged as promising approaches for reducing elevated LDL-C levels. Here, we evaluated the cholesterol lowering efficacy of virus-like particle (VLP) based vaccines that target epitopes found within the LDL receptor (LDL-R) binding domain of PCSK9. In both mice and non-human primates, a bivalent VLP vaccine targeting two distinct epitopes on PCSK9 elicited strong and durable antibody responses and lowered cholesterol levels. In macaques, a VLP vaccine targeting a single PCSK9 epitope was only effective at lowering LDL-C levels in combination with statins, whereas immunization with the bivalent vaccine lowered LDL-C without requiring statin co-administration. These data highlight the efficacy of an alternative, vaccine-based approach for lowering LDL-C.

Estimating human papillomavirus vaccine efficacy from a single-arm trial: proof-of-principle in the Costa Rica Vaccine Trial.

BACKGROUND: The World Health Organization recommends a 1- or 2-dose human papillomavirus (HPV) vaccination schedule for females aged 9 to 20 years. Studies confirming the efficacy of a single dose and vaccine modifications are needed, but randomized controlled trials are costly and face logistical and ethical challenges. We propose a resource-efficient single-arm trial design that uses untargeted and unaffected HPV types as controls. METHODS: We estimated HPV vaccine efficacy (VE) from a single arm by comparing 2 ratios: the ratio of the rate of persistent incident infection with vaccine-targeted HPV 16 and 18 (HPV 16/18) and cross-protected types HPV 31, 33, and 45 (HPV 31/33/45) to vaccine-unaffected types HPV 35, 39, 51, 52, 56, 58, 59, and 66 (HPV 35/39/51/52/56/58/59/66) vs the ratio of prevalence of these types at the time of trial enrollment. We compare VE estimates using only data from the bivalent HPV 16/18 vaccine arm of the Costa Rica Vaccine Trial with published VE estimates that used both the vaccine and control arms. RESULTS: Our single-arm approach among 3727 women yielded VE estimates against persistent HPV 16/18 infections similar to published 2-arm estimates from the trial (according-to-protocol cohort: 91.0% , 95% CI = 82.9% to 95.3% [single-arm] vs 90.9% , 95% CI = 82.0% to 95.9% [2-arm]; intention-to-treat cohort: 41.7%, 95% CI = 32.4% to 49.8% [single-arm] vs 49.0% , 95% CI = 38.1% to 58.1% [2-arm]). VE estimates were also similar in analytic subgroups (number of doses received; baseline HPV serology status). CONCLUSIONS: We demonstrate that a single-arm design yields valid VE estimates with similar precision to a randomized controlled trial. Single-arm studies can reduce the sample size and costs of future HPV vaccine trials while avoiding concerns related to unvaccinated control groups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00128661.

Opportunities for Achieving the Cancer Moonshot Goal of a 50% Reduction in Cancer Mortality by 2047.

On February 2, 2022, President Biden and First Lady Dr. Biden reignited the Cancer Moonshot, setting a new goal to reduce age-standardized cancer mortality rates by at least 50% over the next 25 years in the United States. We estimated trends in U.S. cancer mortality during 2000 to 2019 for all cancers and the six leading types (lung, colorectum, pancreas, breast, prostate, liver). Cancer death rates overall declined by 1.4% per year from 2000 to 2015, accelerating to 2.3% per year during 2016 to 2019, driven by strong declines in lung cancer mortality (-4.7%/year, 2014 to 2019). Recent declines in colorectal (-2.0%/year, 2010-2019) and breast cancer death rates (-1.2%/year, 2013-2019) also contributed. However, trends for other cancer types were less promising. To achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. We reviewed opportunities to prevent, detect, and treat these common cancers that could further reduce population-level cancer death rates and also reduce disparities. SIGNIFICANCE: We reviewed opportunities to prevent, detect, and treat common cancers, and show that to achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. See related commentary by Bertagnolli et al., p. 1049. This article is highlighted in the In This Issue feature, p. 1027.

HPV42, a "Low-Risk" Type, and Digital Papillary Adenocarcinoma.

SUMMARY: Chronic infection by several "high-risk" human papillomavirus (HPV) types has been causally implicated in several forms of anogenital and oropharyngeal cancers. Now, HPV42, which is usually classified as a "low-risk" type, can be listed as the main cause of digital papillary adenocarcinoma, an uncommon malignant tumor of the fingers and toes. See related article by Leiendecker et al., p. 70 (3).

Prospects for preventing cancer with anti-microbial prophylactic vaccines.

Vaccines against cancer-causing microbes could potentially prevent 15% of cancers worldwide and thereby address global disparities in cancer control. To reach this potential, the established hepatitis B virus and human papillomavirus vaccines must be more widely implemented, and effective vaccines against Epstein-Barr virus, hepatitis C virus, and Helicobacter pylori must be developed.

Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose of HPV vaccine in historical cohorts: an immunobridging analysis of a randomised controlled trial.

BACKGROUND: Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9-14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial [CVT] and Institutional Agency for Research on Cancer [IARC] India trial). METHODS: In this immunobridging analysis of an open-label randomised controlled trial, girls were recruited from 54 government schools in Mwanza, Tanzania, into the DoRIS trial. Girls were eligible if they were aged 9-14 years, healthy, and HIV negative. Participants were randomly assigned (1:1:1:1:1:1), using permutated block sizes of 12, 18, and 24, to one, two, or three doses of the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart, Belgium) or the 9-valent vaccine (Gardasil 9, Sanofi Pasteur MSD, Lyon, France). For this immunobridging analysis, the primary objective was to compare geometric mean concentrations (GMCs) at 24 months after one dose in the per-protocol population compared with in historical cohorts: the one-dose 2-valent vaccine group in DoRIS was compared with recipients of the 2-valent vaccine Cervarix from CVT and the one-dose 9-valent vaccine group in DoRIS was compared with recipients of the 4-valent vaccine Gardasil (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) from the IARC India trial. Samples were tested together with virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial vs historical cohort) was predefined as when the lower bound of the 95% CI was greater than 0·50. This study is registered with ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility, of whom 930 were enrolled into DoRIS and 155 each were assigned to one dose, two doses, or three doses of 2-valent vaccine, or one dose, two doses, or three doses of 9-valent vaccine. 154 (99%) participants in the one-dose 2-valent vaccine group (median age 10 years [IQR 9-12]) and 152 (98%) in the one-dose 9-valent vaccine group (median age 10 years [IQR 9-12]) were vaccinated and attended the 24 month visit, and so were included in the analysis. 115 one-dose recipients from the CVT (median age 21 years [19-23]) and 139 one-dose recipients from the IARC India trial (median age 14 years [13-16]) were included in the analysis. At 24 months after vaccination, GMCs for HPV16 IgG antibodies were 22·9 international units (IU) per mL (95% CI 19·9-26·4; n=148) for the DoRIS 2-valent vaccine group versus 17·7 IU/mL (13·9-22·5; n=97) for the CVT (GMC ratio 1·30 [95% CI 1·00-1·68]) and 13·7 IU/mL (11·9-15·8; n=145) for the DoRIS 9-valent vaccine group versus 6·7 IU/mL (5·5-8·2; n=131) for the IARC India trial (GMC ratio 2·05 [1·61-2·61]). GMCs for HPV18 IgG antibodies were 9·9 IU/mL (95% CI 8·5-11·5: n=141) for the DoRIS 2-valent vaccine group versus 8·0 IU/mL (6·4-10·0; n=97) for the CVT trial (GMC ratio 1·23 [95% CI 0·95-1·60]) and 5·7 IU/mL (4·9-6·8; n=136) for the DoRIS 9-valent vaccine group versus 2·2 IU/mL (1·9-2·7; n=129) for the IARC India trial (GMC ratio 2·12 [1·59-2·83]). Non-inferiority of antibody GMCs was met for each vaccine for both HPV16 and HPV18. INTERPRETATION: One dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection. A one-dose schedule would reduce costs, simplify vaccine delivery, and expand access to the vaccine. FUNDING: UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Harnessing Human Papillomavirus' Natural Tropism to Target Tumors.

Human papillomaviruses (HPV) are small non-enveloped DNA tumor viruses established as the primary etiological agent for the development of cervical cancer. Decades of research have elucidated HPV's primary attachment factor to be heparan sulfate proteoglycans (HSPG). Importantly, wounding and exposure of the epithelial basement membrane was found to be pivotal for efficient attachment and infection of HPV in vivo. Sulfation patterns on HSPG's become modified at the site of wounds as they serve an important role promoting tissue healing, cell proliferation and neovascularization and it is these modifications recognized by HPV. Analogous HSPG modification patterns can be found on tumor cells as they too require the aforementioned processes to grow and metastasize. Although targeting tumor associated HSPG is not a novel concept, the use of HPV to target and treat tumors has only been realized in recent years. The work herein describes how decades of basic HPV research has culminated in the rational design of an HPV-based virus-like infrared light activated dye conjugate for the treatment of choroidal melanoma.

Understanding the public health value and defining preferred product characteristics for therapeutic human papillomavirus (HPV) vaccines: World Health Organization consultations, October 2021-March 2022.

The World Health Organization (WHO) global strategy to eliminate cervical cancer (CxCa) could result in >62 million lives saved by 2120 if strategy targets are reached and maintained: 90% of adolescent girls receiving prophylactic human papillomavirus (HPV) vaccine, 70% of women receiving twice-lifetime cervical cancer screening, and 90% of cervical pre-cancer lesions and invasive CxCa treated. However, the cost and complexity of CxCa screening and treatment approaches has hampered scale-up, particularly in low- and middle-income countries (LMICs), and new approaches are needed. Therapeutic HPV vaccines (TxV), which could clear persistent high-risk HPV infection and/or cause regression of pre-cancerous lesions, are in early clinical development and might offer one such approach. During October 2021 to March 2022, WHO, in collaboration with the Bill and Melinda Gates Foundation, convened a series of global expert consultations to lay the groundwork for understanding the potential value of TxV in the context of current CxCa prevention efforts and for defining WHO preferred product characteristics (PPCs) for TxV. WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper reports on the main discussion points and findings from the expert consultations. Experts identified several ways in which TxV might address challenges in current CxCa prevention programmes, but emphasized that the potential value of TxV will depend on their degree of efficacy and how quickly they can be developed and implemented relative to ongoing scale-up of existing interventions. Consultation participants also discussed potential use-cases for TxV, important PPC considerations (e.g., vaccine indications, target populations, and delivery strategies), and critical modelling needs for predicting TxV impact and cost-effectiveness.

Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors.

Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4+ or CD8+ T cells. The MCMV CD8+ T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4+ T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen-specific CD8+ T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8+ T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8+ T cell-peptide epitopes alone or CD4+ T cell-peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen-agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.

Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial.

BACKGROUND: In women vaccinated against human papillomavirus (HPV), reductions in cervical disease and related procedures results in more women having intact transformation zones, potentially increasing the risk of cervical lesions caused by non-vaccine-preventable HPV types, a phenomenon termed clinical unmasking. We aimed to evaluate HPV vaccine efficacy against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) attributed to non-preventable HPV types in the long-term follow-up phase of the Costa Rica HPV Vaccine Trial (CVT). METHODS: CVT was a randomised, double-blind, community-based trial done in Costa Rica. Eligible participants were women aged 18-25 years who were in general good health. Participants were randomly assigned (1:1) to receive an HPV 16 and 18 AS04-adjuvanted vaccine or control hepatitis A vaccine, using a blocked randomisation method (permuted block sizes of 14, 16, and 18). Vaccines in both groups were administered intramuscularly with 0·5 mL doses at 0, 1, and 6 months. Masking of vaccine allocation was maintained throughout the 4-year randomised trial phase, after which participants in the hepatitis A virus vaccine control group were provided the HPV vaccine and exited the study; a screening-only, unvaccinated control group was enrolled. The unvaccinated control group and HPV vaccine group were followed up for 7 years, during which treatment allocation was not masked. One of the prespecified primary endpoints for the long-term follow-up phase was precancers associated with HPV types not prevented by the vaccine, defined as histologically confirmed incident CIN2+ events or CIN3+ events attributed to any HPV type except HPV 16, 18, 31, 33, and 45. Our primary analytical period was years 7-11. Primary analyses were in all participants with at least one follow-up visit and excluded participants with a previous endpoint (ie, modified intention-to-treat cohort). Safety endpoints have been reported elsewhere. This trial is registered with ClinicalTrials.gov, NCT00128661 and NCT00867464. The randomised, masked trial phase is completed; an unmasked subset of women in the HPV-vaccinated group is under active investigation. FINDINGS: Between June 28, 2004, and Dec 21, 2005, 7466 participants were enrolled (HPV vaccine group n=3727 and hepatitis A virus vaccine control group n=3739). Between March 30, 2009, and July 5, 2012, 2836 women enrolled in the new unvaccinated control group. The primary analytical cohort (years 7 to 11) included 2767 participants in the HPV vaccine group and 2563 in the unvaccinated group for the CIN2+ events endpoint assessment and 2826 participants in the HPV vaccine group and 2592 in the unvaccinated control group for the CIN3+ events endpoint assessment. Median follow-up during years 7 to 11 for women included for the CIN2+ events analysis was 52·8 months (IQR 44·0 to 60·7) for the HPV vaccine group and 49·8 months (42·0 to 56·9) for the unvaccinated control group. During years 7 to 11, clinical unmasking was observed with a negative vaccine efficacy against CIN2+ events attributed to non-preventable HPV types (-71·2% [95% CI -164·0 to -12·5]), with 9·2 (95% CI 2·1 to 15·6) additional CIN2+ events attributed to non-preventable HPV types per 1000 HPV-vaccinated participants versus HPV-unvaccinated participants. 27·0 (95% CI 14·2 to 39·9) fewer CIN2+ events irrespective of HPV type per 1000 vaccinated participants were observed during 11 years of follow-up. Vaccine efficacy against CIN3+ events attributed to non-preventable HPV types during years 7 to 11 was -135·0% (95% CI -329·8 to -33·5), with 8·3 (3·0 to 12·8) additional CIN3+ events attributed to non-preventable HPV types per 1000 vaccinated participants versus unvaccinated participants. INTERPRETATION: Higher rates of CIN2+ events and CIN3+ events due to non-preventable HPV types in vaccinated versus unvaccinated participants suggests clinical unmasking could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programmes in screened populations. Importantly, the net benefit of vaccination remains considerable; therefore, HPV vaccination should still be prioritised as primary prevention for cervical cancer. FUNDING: National Cancer Institute and National Institutes of Health Office of Research on Women's Health. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Cancer vaccines.

Given the renewed interest in vaccine development sparked by the COVID-19 pandemic, we are revisiting the current state of vaccine development for cancer prevention and treatment. Experts discuss different vaccine types, their antigens and modes of action, and where we stand on their clinical development, plus the challenges we need to overcome for their broad implementation.

Performance of Cervical Screening a Decade Following HPV Vaccination: The Costa Rica Vaccine Trial.

BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.

Chondroitin Sulfate Proteoglycans Are De Facto Cellular Receptors for Human Papillomavirus 16 under High Serum Conditions.

Human papillomaviruses (HPVs) are nonenveloped double-stranded DNA viruses that utilize heparan sulfate proteoglycans (HSPGs) as initial attachment factors prior to cell entry and infection. While extensively characterized, the selective interaction between HPV and HSPGs is generally studied using standard in vitro conditions, which fail to account for the effects that media additives, such as fetal bovine serum (FBS), can have on viral binding. As environmental conditions and growth factors associated with wound healing are thought to play a role in natural HPV infection, we sought to investigate the effects that serum or platelet extracts could have on the binding and infectivity of HPV. Here, we demonstrate that high concentrations of FBS and human serum greatly inhibit HPV16 binding, and that for FBS, this effect results from the obstruction of cell surface HSPGs by serum-derived heparin-binding proteins (HBPs). Surprisingly, we found that under these conditions, HPV particles utilize 6O-sulfated chondroitin sulfate proteoglycans (CSPGs) as initial binding receptors prior to infection. These findings were corroborated by small interfering RNA (siRNA)-mediated knockdown experiments, as well as through a cancer cell line screen, where we identified a strong association between viral binding in high serum and the expression of chondroitin sulfate biosynthesis genes. Furthermore, HPV binding in the presence of human platelet lysate also demonstrated an increased dependance on CSPGs, suggesting a possible role for these receptor proteoglycans in active wound healing environments. Overall, this work highlights the significant influence that serum/platelet factors can have on virus binding and identifies CSPGs as alternative cell attachment receptors for HPV. IMPORTANCE Heparan sulfate proteoglycans (HSPGs) have previously been identified as primary attachment factors for the initial binding of human papillomaviruses (HPVs) prior to infection. Here, we demonstrate that in vitro, HPV binding to HSPGs is strongly dependent on the surrounding experimental conditions, including the concentration of fetal bovine serum (FBS). We found that high concentrations of FBS can block HSPG-binding sites and cause a dependence on 6O-sulfated chondroitin sulfate proteoglycans (CSPGs) as alternative initial viral receptors. Further, we demonstrate that use of a human-derived alternative to FBS, human platelet lysate, also occludes HSPG-dependent binding, causing a shift toward CSPGs for viral attachment. As HPV infection of basal epithelial cells is thought to occur at sites of microtrauma with exposure to high serum levels and platelet factors, these unexpected findings highlight a possible role for CSPGs as important cellular receptors for the binding and infectivity of HPV in vivo.

HPV16 infection decreases vaccine-induced HPV16 antibody avidity: the CVT trial.

The HPV vaccine has shown sustained efficacy and consistent stabilization of antibody levels, even after a single dose. We defined the HPV16-VLP antibody avidity patterns over 11 years among women who received one- or three doses of the bivalent HPV vaccine in the Costa Rica HPV Vaccine Trial. Absolute HPV16 avidity was lower in women who received one compared to three doses, although the patterns were similar (increased in years 2 and 3 and remained stable over the remaining 8 years). HPV16 avidity among women who were HPV16-seropositive women at HPV vaccination, a marker of natural immune response to HPV16 infection, was significantly lower than those of HPV16-seronegative women, a difference that was more pronounced among one-dose recipients. No differences in HPV16 avidity were observed by HPV18 serostatus at vaccination, confirming the specificity of the findings. Importantly, point estimates for vaccine efficacy against incident, six-month persistent HPV16 infections was similar between women who were HPV16 seronegative and seropositive at the time of initial HPV vaccination for both one-dose and three-dose participants. It is therefore likely that this lower avidity level is still sufficient to enable antibody-mediated protection. It is encouraging for long-term HPV-vaccine protection that HPV16 antibody avidity was maintained for over a decade, even after a single dose.

Rationale and design of a double-blind randomized non-inferiority clinical trial to evaluate one or two doses of vaccine against human papillomavirus including an epidemiologic survey to estimate vaccine efficacy: The Costa Rica ESCUDDO trial.

HPV vaccination of adolescent girls is the most effective measure to prevent cervical cancer. The World Health Organization recommends that adolescent girls receive two doses of vaccine but only a small proportion of girls from regions with the highest disease burden are vaccinated because of cost and logistical considerations. Our Costa Rica HPV Vaccine trial suggested that one dose of the bivalent HPV vaccine provides robust and lasting protection against persistent HPV infections for over a decade. Data from a post-licensure trial of the quadrivalent vaccine in India also suggested that a single dose may be effective in reducing cervical cancer risk. To formally compare one versus two doses of the bivalent and nonavalent HPV vaccines, we implemented a large, randomized, double-blind trial to investigate the non-inferiority of one compared to two vaccine doses in the prevention of new HPV16/18 infections that persist 6 or more months. Bivalent and nonavalent vaccines will be evaluated separately. The trial enrolled and randomized (1:1:1:1 to 1- and 2-dose arms of the bivalent and nonavalent vaccines) 20,330 girls 12 to 16 years old residing in Costa Rica. Trial participants are followed every 6 months for up to 5 years. We also aim to estimate vaccine efficacy by comparing the rates of 6 month persistent infection in unvaccinated women with the rates in the follow-up visits of trial participants. We included one survey of unvaccinated women at the start of the study (N = 4452) and will include another survey concomitant with follow up visits of trial participants at year 4.5 (planned N = 3000). Survey participants attend two visits 6 months appart. Herein, we present the rationale, design, and enrolled study population of the ESCUDDO trial. ClinicalTrials.gov Identifier: NCT03180034.

Human Papillomavirus Vaccines.

Human papillomavirus (HPV) vaccines are among the most effective vaccines available, the first to prevent infection by a mucosatropic sexually transmitted infectious agent and to do so without specific induction of mucosal immunity. Currently available prophylactic HPV vaccines are based on virus-like particles that self-assemble spontaneously from the L1 major capsid protein. The first HPV vaccine was licensed in 2006. All vaccines target HPV-16 and HPV-18, types which cause the majority of HPV-attributable cancers. As of 2020, HPV vaccines had been introduced into national immunization programs in more than 100 countries. Vaccination polices have evolved; most programs target vaccination of young adolescent girls, with an increasing number also including boys. The efficacy and safety found in prelicensure trials have been confirmed by data from national immunization programs. The dramatic impact and effectiveness observed has stimulated interest in ambitious disease reduction goals.