Human Papillomavirus Type Replacement Following the Implementation of HPV Vaccination

Suuren riskin HPV- (human papillomavirus, ihmisen papilloomavirus) infektio on välttämätön kohdunkaulansyövän syy, ja osasyy lukuisissa muissa anogenitaali- ja suu-nielusyövissä. Ennaltaehkäisevän HPV-rokotuksen käyttöönotto ensimmäisen sukupolven rokotteilla, jotka suojaavat HPV-tyypeiltä 16 ja 18, tarjoaa mahdollisuuden kontrolloida HPV16/18 infektioita ja eliminoida niihin liittyvät syövät. Ensimmäisen sukupolven rokotteet kuitenkin kattavat vain kaksi 12:sta kansainvälisen syöväntutkimuslaitoksen (IARC) luokittelemasta korkean riskin HPV-tyypistä. Rokotusten kohdistuminen vain osaan jonkin patogeenin alatyypeistä on johtanut ei-maalitettujen alatyyppien yleistymiseen – ilmiöön, joka tunnetaan tyyppikorvautuvuutena. HPV-rokotusten aiheuttamasta korkean riskin HPV-tyyppien korvautumisesta ei-maalitetuilla HPV-tyypeillä on nostanut huolen siihen, että mitätöisikö tyyppikorvautuminen HPV-rokotuksen vaikuttavuuden. Väitöskirjassani olen arvioinut ja verrannut rokottamalla aikaansaatujen neutraloivien ja risti-neutraloivien vasta-aineresponssien kestävyyttä kahden ensimmäisen sukupolven, kaksi- ja nelivalenttisen, rokotteen välillä seuraamalla rokotetrialeihin osallistuneita kahta suomalaista kohorttia väestöpohjaisen äitiysneuvolapohjaisen seerumipankin (FMC) avulla. Havaitsin, että sekä kaksi- että nelivalenttinen rokote saavat aikaan kestävän neutraloivan vasta-aineresponssin HPV16 ja HPV18 vastaan kolme annosta saaneilla rokotetuilla naisilla. Nelivalenttista rokotetta saaneista naisista 15% oli HPV18 seronegatiivisia, joten heiltä ei voitu mitata neutraloivia HPV18 vasta-aineita kun taas 100% kaksivalenttista rokotetta saaneista kehitti HPV18 vasta-aineita. Tämän lisäksi huomattavia eroja näiden kahden rokotekohortin välillä oli havaittavissa: HPV31, 33, 45, 52 ja 58 serokonversio oli yleisempää kaksivalenttista rokotetta saaneilla Arvioin tämän jälkeen ekologisen HPV16/18 lokeron tyhjentymistä, ja HPV- rokotuksen suoraa ja epäsuoraa suojavaikutusta. Tämä on tapahtunut seuraten aktiivisesti ja passiivisesti suomalaista väestöpohjaista paikkakuntasatunnaistettua tutkimusta, jossa arvioitiin poikien ja tyttöjen verrattuna vain tyttöjen HPV-rokotusstrategioiden vaikuttavuutta. Havaitsin ekologisen HPV16/18 lokeron tyhjentyneen parhaiten niiden rokottamattomien joukossa, jotka asuivat poikien ja tyttöjen rokotuspaikkakunnilla. Merkitsevä sekä HPV16 että HPV18 esiintymisen lasku oli todettavissa näillä paikkakunnilla. HPV16 lokeron ei voitu todeta tyhjentyneen vain tyttöjen rokotuspaikkakunnilla. HPV-rokotettujen joukossa HPV16 ja HPV18 eivät juurikaan esiintyneet, myös HPV31, 33 ja 45 esiintyminen oli huomattavasti laskenut verrattuna hepatiitti B (HBV)-rokotettuihin verrokkeihin. Viimeiseksi olen arvioinut ei-rokotetyyppien ilmentymistä sekä HPV-rokotetuilla että rokottamattomilla käyttäen aktiivista ja passiivista saman paikkakuntasatunnaistetun tutkimuksen seurantaa määrittääkseni onko ei-rokotetyyppien ilmentyminen yleistynyt hyödyntäen (osittain tyhjentynyttä) HPV16/18 ekologista lokeroa tavalla, joka merkitsisi tyyppikorvautuvuutta. Havaitsin toistettavia yleistymisiä HPV51 ja jossain määrin HPV58 suhteen. Tämän lisäksi yksittäisiä HPV59 ja HPV66 nousuja oli todettavissa. Mikään näistä havainnoista ei kuitenkaan ollut toistettavissa paikkakunnilla rokotusta ennen tai sen jälkeen asuneiden passiivisessa seurannassa. HPV68 (tyyppi, jota ei mitattu aktiivisessa seurannassa) esiintymisessä havaitsimme nousun rokotuksen jälkeisenä aikana tyttöjen paikkakunnilla. Samankaltainen nousu oli kuitenkin havaittavissa myös rokottamattomilla naisilla kontrollipaikkakunnilla, mikä viittasi siihen, että nousu ei todennäköisesti ollut HPV-rokotuksen aikaansaamasta tyyppikorvautuvuudesta johtuvaa. Kaiken kaikkiaan havaitsin, että molemmat ensimmäisen sukupolven rokotteet saavat useimmilla naisilla aikaan korkean ja kestävän neutraloivien HPV16/18 vasta-aineiden tason. Kaksivalenttinen rokote sai aikaan useammin ristisuojaavia neutraloivia vasta-aineita kuin nelivalenttinen rokote. Löysin merkitsevän ekologisen lokeron tyhjentymisen (myös HPV16 suhteen) poikien ja tyttöjen rokotuksen seurauksena jo keskikorkealla rokotuskattavuudella. Tästä lokeron tyhjentymisestä huolimatta en löytänyt selviä, yksikäsitteisiä merkkejä ei-rokotetyyppien lisääntyneestä ilmentymisestä, joka olisi kiistatta johtunut HPV-rokotuksen aiheuttamasta tyyppikorvautuvuudesta. Tästä syystä jatkuva ei-rokotteeseen kuuluvien HPV-tyyppien seuranta on jatkossa edelleen tärkeää.Infection with high-risk human papillomavirus (HPV) is a necessary cause of cervical cancers and an associated cause of several other anogenital and oropharyngeal cancers. The beginning of the era of prophylactic human papillomavirus vaccination, via the implementation of efficacious first-generation vaccines targeting the two most high-risk oncogenic HPV types 16 and 18, offers the opportunity for the control of HPV16/18 infection and elimination of HPV16/18 associated cancers. The first-generation vaccines, however, target only 2 of 12 IARC classified high risk oncogenic HPV types. Previously vaccination of a targeted subset of strains of a pathogen has in some instances led to an increase in the non-targeted strains in a phenomenon known as serotype (or genotype) replacement. Therefore, there has been concern that targeted HPV vaccination might induce HPV genotype replacement by the non-vaccine targeted high risk HPV types, potentially undermining the impact of HPV vaccination. In this dissertation, we have evaluated and compared the sustainability of vaccine-induced neutralising and cross-neutralising antibody response of the two first generation vaccines, the bivalent and the quadrivalent vaccine, by following up two cohorts of vaccinated Finnish trial participants in the population-representative Finnish maternity cohort serum biobank. We have then evaluated the degree of HPV16/18 niche clearance, both the direct and indirect impact of vaccination, via active and passive follow-up of the population-based Finnish community randomised trial of HPV vaccination strategy with moderate vaccination coverage (gender-neutral vaccination versus girls only HPV vaccination using the bivalent HPV vaccine). Subsequently we have evaluated the occurrence of the non-vaccine HPV types among both HPV vaccinated and unvaccinated women via the same active and passive follow-up of the community randomised trial, to assess whether the non- vaccine types increased in occurrence and took advantage of the cleared partially cleared HPV16/18 niche (measured as decreased occurrence) in a manner indicative of type replacement. We further investigated the same, among the high-risk taking core group, where transmission dynamics are greater and early indications of type replacement may be observed. We found that both the bivalent and the quadrivalent vaccines induce a sustainable neutralising antibody response against HPV16 and HPV18 among women vaccinated with three doses of the respective vaccine. However, among the quadrivalent vaccine recipients 15% of the women were found to be seronegative to HPV18 with no detectable HPV18 neutralizing antibodies, whilst among the bivalent vaccine recipients 100% had seroconverted to HPV18. Notable differences in the cross-neutralising antibodies response were observed between the two vaccinated cohorts, with seroconversion to HPV31, 33, 45, 52, and 58 being higher among the bivalent vaccine recipients in comparison to the quadrivalent vaccine recipients. Following the community randomised trial, we observed the greatest HPV16/18 niche clearance among the unvaccinated residents of the gender-neural trial arm communities. Significant reduction of both HPV16 and HPV18 prevalence was observed after gender-neutral HPV vaccination. No HPV16 niche clearance in unvaccinated residents was observed in the girls-only vaccination arm communities. Among the HPV vaccinated participants, the prevalence of vaccine targeted HPV16 and 18 was almost negligible, whilst the prevalence of HPV31, 33 and 45 were also markedly reduced in comparison to the HBV vaccinated controls. When evaluating the occurrence of the non-vaccine HPV types via the active follow-up of the community randomised trial we observed consistent increases in HPV51, and some indications of increased HPV58 among the participants from the interventions. However, these increases generally stemmed from the older birth cohort. Additionally, some sporadic inconsistent increases in HPV39 and 66 were observed. However, during the passive follow up among the unvaccinated women resident in the trial communities pre- and post- vaccination era, none of these findings were replicated. We observed an increase post-vaccination in the seroprevalence (cumulative incidence) of HPV68 (a type not measured in the active follow-up) among the residents from the girls-only intervention communities. However, a similar HPV68 seroprevalence increase was also observed among the unvaccinated women from the control arm communities, suggesting that this increase was unlikely to be due to vaccine-induced type replacement. Overall, we observed that both first generation vaccines induce a high level of sustainable HPV16/18 neutralising antibodies over time among women, whilst the bivalent vaccine provided a higher prevalence of cross-protective neutralising antibodies as compared to the quadrivalent vaccine. We further found significant niche clearance (also HPV16 niche clearance) following gender-neutral vaccination even with moderate vaccination coverage. However, despite this observed niche clearance, we found no clear, decisive signs of increased non-vaccine occurrence which could irrefutably be due to vaccine-induced type replacement. These findings were specific to the study setting (vaccination coverage, the vaccine used and the duration of follow-up), thereby, continued surveillance of the non-vaccine HPV types will remain crucial in the future

Cognitive and emotional factors associated with the desire to cease non-suicidal self-injury

Background: Due to cognitive and emotional differences between individuals who have and have not stopped self-injuring, we explored these in the context of desire to stop. Method: Australian university students (n = 374) completed cognitive and emotional measures. Comparisons were made between those who had self-injured in the past 12 months and those who had not, and between individuals who reported wanting to stop self-injuring and those who did not. Results: Approximately 20% of participants did not want to stop self-injuring. Cognitive emotional factors (psychological distress, self-efficacy to resist, difficulties regulating emotion, interpersonal functions, and outcome expectancies) differentiated individuals who had and had not stopped, but could not explain differences in desire to stop. Conclusion: Factors associated with desire to stop are not the same as factors underlying behavioural cessation. Motivational approaches to changes in self-injurious behaviour would be beneficial for clinicians and their clients

Robots in special education: reasons for low uptake

Purpose: This paper identifies the main reasons for low uptake of robots in Special Education, obtained from an analysis of previous studies that used robots in the area, and from interviewing Special Education teachers about the topic. Design/methodology/approach: An analysis of 18 studies that used robots in Special Education was performed, and the conclusions were complemented and compared with the feedback from interviewing 13 Special Education teachers from Spain and UK about the reasons they believed caused the low uptake of robots in Special Education classrooms. Findings: Five main reasons why Special Education schools do not normally use robots in their classrooms were identified: the inability to acquire the system due to its price or availability; its difficulty of use; the low range of activities offered; the limited ways of interaction offered; and the inability to use different robots with the same software. Originality/value: Previous studies focused on exploring the advantages of using robots to help children with Autistic Spectrum Conditions and Learning Disabilities. This study takes a step further and looks into the reasons why, despite the benefits shown, robots are rarely used in real-life settings after the relevant study ends. The authors also present a potential solution to the issues found: involving end users in the design and development of new systems using a user-centred design approach for all the components, including methods of interaction, learning activities, and the most suitable type of robots

Ecological diversity profiles of non-vaccine-targeted HPVs after gender-based community vaccination efforts

The long-term effect of population-level human papillomavirus (HPV) vaccination on the viral ecology of the untargeted HPVs is poorly understood. We performed an 8-year follow-up of 33 communities randomized to gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and control communities without HPV vaccination. The 1992/93 and 1994 birth cohorts were invited in school years 2007/8 and 2008/9. Follow-up cervico-vaginal sampling at 18 and 22 years of age, 4 and 8 years post-vaccination, respectively, were attended by 11,396 and 5,602 participants. HPV types 6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68 were genotyped and used for the community-level ecological diversity estimations. Gender-neutral vaccination communities with a stronger herd immunity than girls-only vaccination communities show a significantly increased HPV α-diversity (p = 1.1 × 10−8) from 4 to 8 years post-vaccination, despite the clearance of the vaccine-targeted HPVs in these communities. This likely sign of niche occupation by the non-vaccine-targeted HPVs will potentially affect the future cervical cancer screening programs but should not interfere with the WHO mission to eliminate cervical cancer.Peer reviewe

Head-to-Head Comparison of Bi- and Nonavalent Human Papillomavirus Vaccine-Induced Antibody Responses

For head-to-head comparison of human papillomavirus (HPV) antibody levels induced by different vaccines, 25-year-old vaccine-naive women were given either the bivalent (n = 188) or the nonavalent HPV vaccine (n = 184). Six months after vaccination antibodies against pseudovirions from 17 different HPV types (HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68/73) were measured. Antibodies against HPV16/18 were higher after bivalent HPV vaccination (mean international units [IU] 1140.1 and 170.5 for HPV16 and 18, respectively) than after nonavalent vaccination (265.1 and 22.3 IUs, respectively). The bivalent vaccine commonly induced antibodies against the nonvaccine HPV types 31/33/35/45 or 58. The nonavalent vaccine induced higher antibodies against HPV6/11/31/33/45/52/58 and 35.publishedVersionPeer reviewe

Baseline findings and safety of infrequent vs. frequent screening of human papillomavirus vaccinated women

Less frequent cervical cancer screening in human papillomavirus (HPV) vaccinated birth cohorts could produce considerable savings without increasing cervical cancer incidence and loss of life-years. We report here the baseline findings and interim results of safety and accuracy of infrequent screening among HPV16/18 vaccinated females. The entire 1992-1994 birth-cohorts (30,139 females) were invited to a community-randomized HPV16/18-vaccination trial. A total of 9,482 female trial participants received HPV16/18-vaccination in 2007-2009 at age of 13-15. At age 22, 4,273 (45%) of these females consented to attend a randomized trial on frequent (ages 22/25/28; Arm 1: 2,073 females) vs. infrequent screening (age 28; Arm 2: 2,200 females) in 2014-2017. Females (1,329), who had got HPV16/18 vaccination at age 18 comprised the safety Arm 3. Baseline prevalence and incidence of HPV16/18 and other high-risk HPV types were: 0.5% (53/1,000 follow-up years, 10(4)) and 25% (2,530/10(4)) in the frequently screened Arm 1; 0.2% (23/10(4)) and 24% (2,413/10(4)) in the infrequently screened Arm 2; and 3.1% (304/10(4)) and 23% (2,284/10(4)) in the safety Arm 3. Corresponding prevalence of HSIL/ASC-H and of any abnormal cytological findings were: 0.3 and 4.2% (Arm 1), 0.4 and 5.3% (Arm 2) and 0.3 and 4.7% (Arm 3). Equally rare HSIL/CIN3 findings in the infrequently screened safety Arm A3 (0.4%) and in the frequently screened Arm 1 (0.4%) indicate no safety concerns on infrequent screening despite the up to 10 times higher HPV16/18 baseline prevalence and incidence in the former.Peer reviewe

The C3-V4 region is a major target of autologous neutralizing antibodies in human immunodeficiency virus type 1 subtype C Infection.

The early autologous neutralizing antibody response in human immunodeficiency virus type 1 (HIV-1) subtype C infections is often characterized by high titers, but the response is type specific with little to no cross-neutralizing activity. The specificities of these early neutralizing antibodies are not known; however, the type specificity suggests that they may target the variable regions of the envelope. Here, we show that cross-reactive anti-V3 antibodies developed within 3 to 12 weeks in six individuals but did not mediate autologous neutralization. Using a series of chimeric viruses, we found that antibodies directed at the V1V2, V4, and V5 regions contributed to autologous neutralization in some individuals, with V1V2 playing a more substantial role. However, these antibodies did not account for the total neutralizing capacity of these sera against the early autologous virus. Antibodies directed against the C3-V4 region were involved in autologous neutralization in all four sera studied. In two sera, transfer of the C3-V4 region rendered the chimera as sensitive to antibody neutralization as the parental virus. Although the C3 region, which contains the highly variable α2-helix was not a direct target in most cases, it contributed to the formation of neutralization epitopes as substitution of this region resulted in neutralization resistance. These data suggest that the C3 and V4 regions combine to form important structural motifs and that epitopes in this region are major targets of the early autologous neutralizing response in HIV-1 subtype C infection

Scientific approaches toward improving cervical cancer elimination strategies

At the 2023 EUROGIN workshop scientific basis for strategies to accelerate the elimination of cervical cancer and its causative agent, human papillomavirus (HPV) were reviewed. Although some countries have reached key performance indicators toward elimination (>90% of girls HPV vaccinated and >70% of women HPV screened), most are yet to reach these targets, implying a need for improved strategies. Gender-neutral vaccination, even with moderate vaccination coverage was highlighted as a strategy to achieve elimination more rapidly. It is more resilient against major disturbances in vaccination delivery, such as what happened during the coronavirus pandemic. Further, an analysis of ethical/legal issues indicated that female-restricted vaccination is problematic. Extended catch-up of vaccination with concomitant screening, and outreach to vulnerable groups were highlighted. Although birth cohorts with high coverage of HPV vaccination at school are protected against HPV, and HPVs have a very low reproductive rate in women above age 35, adult women below age 30 have inadequate direct protection. In addition to herd protection from gender-neutral vaccination, this group can be protected by offering concomitant catch-up HPV vaccination and HPV screening. Furthermore, hepatitis B vaccination experiences indicate that elimination cannot be achieved without prioritizing vulnerable/migrant populations. The long-lasting durability of vaccination-induced antibody responses suggests prolonged protection with HPV vaccines when adequately administrated. Finally, cost-effectiveness modelling suggests that high-coverage HPV vaccination in multiple population segments will be resource-saving due to reduced need for screening. In summary, the workshop found that strategically optimal deployment of vaccination will accelerate elimination of HPV and cervical cancer.Peer reviewe

Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers : population-based follow-up of a cluster-randomised trial

Background Human papillomavirus (HPV) vaccination protects against HPV, a necessary risk factor for cervical cancer. We now report results from population-based follow-up of randomised cohorts that vaccination provides HPV-type-specific protection against invasive cancer. Methods Individually and/or cluster randomised cohorts of HPV-vaccinated and non-vaccinated women were enrolled in 2002-2005. HPV vaccine cohorts comprised originally 16-17 year-old HPV 16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2465) and HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866). Altogether, 3341 vaccines were followed by the Finnish Cancer Registry in the same way as 16 526 non-HPV-vaccinated controls. The control cohort stemmed from 15 665 originally 18-19 years-old women enrolled in 2003 (6499) or 2005 (9166) and 861 placebo recipients of the FUTURE II trial. The follow-up started 6 months after the clinical trials in 2007 and 2009 and ended in 2019. It was age aligned for the cohorts. Findings During a follow-up time of up to 11 years, we identified 17 HPV-positive invasive cancer cases (14 cervical cancers, 1 vaginal cancer, 1 vulvar cancer and 1 tongue cancer) in the non-HPV-vaccinated cohorts and no cases in the HPV-vaccinated cohorts. HPV typing of diagnostic tumour blocks found HPV16 in nine cervical cancer cases, HPV18, HPV33 and HPV52 each in two cases and HPV45 in one cervical cancer case. The vaginal, vulvar and tongue cancer cases were, respectively, positive for HPV16, HPV52/66 and HPV213. Intention-to-treat vaccine efficacy against all HPV-positive cancers was 100% (95% CI 2 to 100, p Interpretation Vaccination is effective against invasive HPV-positive cancer.Peer reviewe

Health inequalities at the intersection of multiple social determinants among under five children residing Nairobi urban slums: an application of multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA)

In this analysis we examine through an intersectionality lens how key social determinants of health (SDOH) are associated with health conditions among under-five children (<5y) residing in Nairobi slums, Kenya. We used cross-sectional data collected from Nairobi slums between June and November 2012 to explore how multiple interactions of SDoH shape health inequalities in slums. We applied multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA) approach. We constructed intersectional strata for each health condition from combinations of significant SDoH obtained using univariate analyses. We then estimated the intersectional effects of health condition in a series of MAIHDA logistic regression models distinguishing between additive and interaction effects. We quantified discriminatory accuracy (DA) of the intersectional strata by means of the variance partitioning coefficient (VPC) and the area under the receiver operating characteristic curve (AUC-ROC). The total participants were 2,199 <5y, with 120 records (5.5%) dropped because health conditions were recorded as “not applicable”. The main outcome variables were three health conditions: 1) whether a child had diarrhea or not, 2) whether a child had fever or not, and 3) whether a child had cough or not in the previous two weeks. We found non-significant intersectional effects for each health condition. The head of household ethnic group was significantly associated with each health condition. We found good DA for diarrhea (VPC = 9.0%, AUC-ROC = 76.6%) an indication of large intersectional effects. However, fever (VPC = 1.9%, AUC-ROC = 66.3%) and cough (VPC = 0.5%, AUC-ROC = 61.8%) had weak DA indicating existence of small intersectional effects. Our study shows pathways for SDoH that affect diarrhea, cough, and fever for <5y living in slums are multiplicative and shared. The findings show that <5y from Luo and Luhya ethnic groups, recent migrants (less than 2 years), and households experiencing CHE are more likely to face worse health outcomes. We recommend relevant stakeholders to develop strategies aimed at identifying these groups for targeted proportionate universalism based on the level of their need