Immunogenicity, safety, and efficacy of the HPV vaccines among people living with HIV: A systematic review and meta-analysis

Background: Vaccines have been demonstrated to protect against high-risk human papillomavirus infection (HPV), including HPV-16/18, and cervical lesions among HIV negative women. However, their efficacy remains uncertain for people living with HIV (PLHIV).We systematically reviewed available evidence on HPV vaccine on immunological, virological, or other biological outcomes in PLHIV. Methods: We searched five electronic databases (PubMed, Medline and Embase, clinicaltrials.gov and the WHO clinical trial database) for longitudinal prospective studies reporting immunogenicity, virological, cytological, histological, clinical or safety endpoints following prophylactic HPV vaccination among PLHIV. We included studies published by February 11th, 2021. We summarized results, assessed study quality, and conducted meta-analysis and subgroup analyses, where possible. Findings: We identified 43 publications stemming from 18 independent studies (Ns =18), evaluating the quadrivalent (Ns =15), bivalent (Ns =4) and nonavalent (Ns =1) vaccines. A high proportion seroconverted for the HPV vaccine types. Pooled proportion seropositive by 28 weeks following 3 doses with the bivalent, quadrivalent, and nonavalent vaccines were 0.99 (95% confidence interval: 0.95-1.00, Ns =1), 0.99 (0.98-1.00, Ns =9), and 1.00 (0.99-1.00, Ns =1) for HPV-16 and 0.99 (0.96-1.00, Ns =1), 0.94 (0.91-0.96, Ns =9), and 1.00 (0.99-1.00, Ns =1) for HPV-18, respectively. Seropositivity remained high among people who received 3 doses despite some declines in antibody titers and lower seropositivity over time, especially for HPV-18, for the quadrivalent than the bivalent vaccine, and for HIV positive than negative individuals. Seropositivity for HPV-18 at 29-99 weeks among PLHIV was 0.72 (0.66-0.79, Ns =8) and 0.96 (0.92-0.99, Ns =2) after 3 doses of the quadrivalent and bivalent vaccine, respectively and 0.94 (0.90-0.98, Ns =3) among HIV-negative historical controls. Evidence suggests that the seropositivity after vaccination declines over time but it can lasts at least 2-4 years. The vaccines were deemed safe among PLHIV with few serious adverse events. Evidence of HPV vaccine efficacy against acquisition of HPV infection and/or associated disease from the eight trials available was inconclusive due to the low quality. Interpretation: PLHIV have a robust and safe immune response to HPV vaccination. Antibody titers and seropositivity rates decline over time but remain high. The lack of a formal correlate of protection and efficacy results preclude definitive conclusions on the clinical benefits. Nevertheless, given the burden of HPV disease in PLHIV, although the protection may be shorter or less robust against HPV-18, the robust immune response suggests that PLHIV may benefit from receiving HPV vaccination after acquiring HIV. Better quality studies are needed to demonstrate the clinical efficacy among PLHIV. Funding: World Health Organization. MRC Centre for Global Infectious Disease Analysis, Canadian Institutes of Health Research, UK Medical Research Council (MRC)

Estimating the effect of HIV on cervical cancer elimination in South Africa: comparative modelling of the impact of vaccination and screening

Background In 2020, the World Health Organization (WHO) launched its initiative to eliminate cervical cancer as a public health problem. To inform global efforts for countries with high HIV and cervical cancer burden, we assessed the impact of human papillomavirus (HPV) vaccination and cervical cancer screening and treatment in South Africa, on cervical cancer and the potential for achieving elimination before 2120, considering faster HPV disease progression and higher cervical cancer risk among women living with HIV(WLHIV) and HIV interventions. Methods Three independent transmission-dynamic models simulating HIV and HPV infections and disease progression were used to predict the impact on cervical cancer incidence of three scenarios for all women: 1) girls' vaccination (9–14 years old), 2) girls' vaccination plus 1 lifetime cervical screen (at 35 years), and 3) girls’ vaccination plus 2 lifetime cervical screens (at 35 and 45 years) and three enhanced scenarios for WLHIV: 4) vaccination of young WLHIV aged 15–24 years, 5) three-yearly cervical screening of WLHIV aged 15–49 years, or 6) both. Vaccination assumed 90% coverage and 100% lifetime protection with the nonavalent vaccine (against HPV-16/18/31/33/45/52/58). Cervical cancer screening assumed HPV testing with uptake increasing from 45% (2023), 70% (2030) to 90% (2045+). We also assumed that UNAIDS 90-90-90 HIV treatment and 70% male circumcision targets are reached by 2030. We examined three elimination thresholds: age-standardised cervical cancer incidence rates below 4 or 10 per 100,000 women-years, and >85% reduction in cervical cancer incidence rate. We conducted sensitivity analyses and presented the median age-standardised predictions of outcomes of the three models (minimum–maximum across models). Findings Girls' vaccination could reduce age-standardised cervical cancer incidence from a median of 47.6 (40.9–79.2) in 2020 to 4.5 (3.2–6.3) per 100,000 women-years by 2120, averting on average ∼4% and ∼46% of age-standardised cumulative cervical cancer cases over 25 and 100 years, respectively, compared to the basecase. Adding 2 lifetime screens helped achieve elimination over the century among all women (2120 cervical cancer incidence: 3.6 (1.9–3.6) per 100,000 women-years), but not among WLHIV (10.8 (5.3–11.6)), and averted more cumulative cancer cases overall (∼45% over 25 years and ∼61% over 100 years compared to basecase) than girls' vaccination alone. Adding three-yearly cervical screening among WLHIV (to girls' vaccination and 2 lifetime cervical screens) further reduced age-standardised cervical cancer incidence to 3.3 (1.8–3.6) per 100,000 women-years overall and to 5.2 (3.9–8.5) among WLHIV by 2120 and averted on average 12–13% additional cumulative cancer cases among all women and 21–24% among WLHIV than girls’ vaccination and 2 lifetime cervical screens over 25 years or longer. Long-term vaccine protection and using the nonavalent vaccine was required for elimination. Interpretation High HPV vaccination coverage of girls and 2 lifetime cervical screens could eliminate cervical cancer among women overall in South Africa by the end of the century and substantially decrease cases among all women and WLHIV over the short and medium term. Cervical cancer elimination in WLHIV would likely require enhanced prevention strategies for WLHIV. Screening of WLHIV remains an important strategy to reduce incidence and alleviate disparities in cervical cancer burden between women with and without HIV, despite HIV interventions scale-up. Funding World Health Organization. National Cancer Institute, National Institutes of Health. MRC Centre for Global Infectious Disease Analysis, UK Medical Research Council. National Institute of Child Health and Human Development research. Cancer Association of South Africa. Canadian Institutes of Health Research and the Fonds de recherche du Québec – Santé research

Monitoring the mortality impact of COVID-19 in Europe: what can be learned from 2009 influenza H1N1p mortality studies?

Objectives Understanding the proportion of pandemic deaths captured as "laboratory-confirmed" deaths is crucial. We assessed the ability of laboratory-confirmed deaths to capture mortality in the EU during the 2009 pandemic, and examined the likelihood that these findings are applicable to the SARS-CoV-2 pandemic. Methods We present unpublished results from the Global Pandemic Mortality (GLaMOR) project, in which country-specific mortality estimates were made for the 2009 influenza H1N1p pandemic. These estimates were compared to laboratory-confirmed deaths during the 2009 pandemic to estimate the ability of surveillance systems to capture pandemic mortality. Results For the 2009 influenza H1N1p pandemic, we estimated that the proportion of true pandemic deaths captured by laboratory-confirmed deaths was approximately 67%. Several differences (e.g. age groups affected) between the two pandemics make it unlikely that this capture rate will be equally high for SARS-CoV-2. Conclusion The surveillance of laboratory-confirmed deaths in the EU during the 2009 pandemic was more accurate than previously assumed. We hypothesize that this method is less reliable for SARS-CoV-2. Near-real-time excess all-cause mortality estimates, routinely compiled by EuroMOMO, probably form a better indicator of pandemic mortality. We urge more countries to join this project and that national level absolute mortality numbers are presented

Temporal variations in respiratory syncytial virus epidemics, by virus subtype, 4 countries.

Temporal variation of respiratory syncytial virus (RSV) epidemics was recently reported to be determined by the dominant RSV subtype. However, when we repeated the analysis for 4 countries in the Northern and Southern Hemispheres, the dominant subtype did not seem to affect temporal variation of RSV epidemics

The impact of the SARS-CoV-2 pandemic on global influenza surveillance: insights from 18 National Influenza Centers based on a survey conducted between November 2021 and March 2022.

Background National Influenza Centers (NICs) have played a crucial role in the surveillance of SARS-CoV-2. The FluCov project, covering 22 countries, was initiated to monitor the impact of the SARS-CoV-2 pandemic on influenza activity. Methods This project consisted of an epidemiological bulletin and NIC survey. The survey, designed to assess the impact of the pandemic on the influenza surveillance system, was shared with 36 NICs located across 22 countries. NICs were invited to reply between November 2021 and March 2022. Results We received 18 responses from NICs in 14 countries. Most NICs (76%) indicated that the number of samples tested for influenza decreased. Yet, many NICs (60%) were able to increase their laboratory testing capacity and the "robustness" (e.g., number of sentinel sites) (59%) of their surveillance systems. In addition, sample sources (e.g., hospital or outpatient setting) shifted. All NICs reported a higher burden of work following the onset of the pandemic, with some NICs hiring additional staff or partial outsourcing to other institutes or departments. Many NICs anticipate the future integration of SARS-CoV-2 surveillance into the existing respiratory surveillance system. Discussion The survey shows the profound impact of SARS-CoV-2 on national influenza surveillance in the first 27 months of the pandemic. Surveillance activities were temporarily disrupted, whilst priority was given to SARS-CoV-2. However, most NICs have shown rapid adaptive capacity underlining the importance of strong national influenza surveillance systems. These developments have the potential to benefit global respiratory surveillance in the years to come; however, questions about sustainability remain

Global and national influenza-associated hospitalisation rates: Estimates for 40 countries and administrative regions.

Background WHO estimates that seasonal influenza epidemics result in three to five million cases of severe illness (hospitalisations) every year. We aimed to improve the understanding of influenza-associated hospitalisation estimates at a national and global level. Methods We performed a systematic literature review of English- and Chinese-language studies published between 1995 and 2020 estimating influenza-associated hospitalisation. We included a total of 127 studies (seven in Chinese) in the meta-analysis and analyzed their data using a logit-logistic regression model to understand the influence of five study factors and produce national and global estimates by age groups. The five study factors assessed were: 1) the method used to calculate the influenza-associated hospitalisation estimates (rate- or time series regression-based), 2) the outcome measure (divided into three envelopes: narrow, medium, or wide), 3) whether every case was laboratory-confirmed or not, 4) whether the estimates were national or sub-national, 5) whether the rates were based on a single year or multiple years. Results The overall pooled influenza-associated hospitalisation rate was 40.1 (95% confidence interval (CI) = 23.3-69.1) per 100 000 persons, with rates varying substantially by age: 137.8 (95% CI = 70.6-268.7) in children aged 0-4 years and 71.6 (95% CI = 39.9-127.7) in the elderly aged >65 years. The overall pooled hospitalisation rates varied by calculation method; for all ages, the rates were significantly higher when they were based on rate-based methods or calculated on a single season and significantly lower when cases were laboratory-confirmed. The national hospitalisation rates (all ages) varied considerably, ranging from 11.7 (95% CI = 3.8-36.3) per 100 000 in New Zealand to 122.1 (95% CI = 41.5-358.4) per 100 000 in India (all age estimates). Conclusions Using the pooled global influenza-associated hospitalisation rate, we estimate that seasonal influenza epidemics result in 3.2 million cases of severe illness (hospitalisations) per annum. More extensive analyses are required to assess the influence of other factors on the estimates (e.g. vaccination and dominant virus (sub)types) and efforts to harmonize the methods should be encouraged. Our study highlights the high rates of influenza-associated hospitalisations in children aged 0-4 years and the elderly aged 65+ years

What is the burden of heterosexually-acquired HIV due to HSV-2? Global and regional model-based estimates of the proportion and number of HIV infections attributable to HSV-2 infection

Background: Biological and epidemiological evidence suggest that herpes simplex virus type 2 (HSV-2) elevates HIV acquisition and transmission risks. We improved previous estimates of the contribution of HSV-2 to HIV infections by using a dynamic transmission model.Setting: World Health Organization regions.Methods: We developed a mathematical model of HSV-2/HIV transmission among 15- to 49-year-old heterosexual, non–drug-injecting populations, calibrated using region-specific demographic and HSV-2/HIV epidemiological data. We derived global and regional estimates of the contribution of HSV-2 to HIV infection over 10 years [the transmission population-attributable fraction (tPAF)] under 3 additive scenarios, assuming: (1) HSV-2 increases only HIV acquisition risk (conservative); (2) HSV-2 also increases HIV transmission risk (liberal); and (3) HIV or antiretroviral therapy (ART) also modifies HSV-2 transmission risk, and HSV-2 decreases ART effect on HIV transmission risk (fully liberal).Results: Under the conservative scenario, the predicted tPAF was 37.3% (95% uncertainty interval: 33.4%–43.2%), and an estimated 5.6 (4.5–7.0) million incident heterosexual HIV infections were due to HSV-2 globally over 2009–2018. The contribution of HSV-2 to HIV infections was largest for the African region [tPAF = 42.6% (38.0%–51.2%)] and lowest for the European region [tPAF = 11.2% (7.9%–13.8%)]. The tPAF was higher among female sex workers, their clients, and older populations, reflecting their higher HSV-2 prevalence. The tPAF was approximately 50% and 1.3- to 2.4-fold higher for the liberal or fully liberal scenario than the conservative scenario across regions.Conclusion: HSV-2 may have contributed to at least 37% of incident HIV infections in the past decade worldwide, and even more in Africa, and may continue to do so despite increased ART access unless future improved HSV-2 control measures, such as vaccines, become available.</h4

The global epidemiology of RSV in the community and hospitalized care: findings from 15 countries.

Background Respiratory syncytial virus (RSV) is one of the leading causes of acute respiratory tract infections. To optimize control strategies, a better understanding of the global epidemiology of RSV is critical. To this end, we initiated the Global Epidemiology of RSV in Hospitalized and Community care study (GERi). Methods Focal points from 44 countries were approached to join GERi and share detailed RSV surveillance data. Countries completed a questionnaire on the characteristics of their surveillance system. Results Fifteen countries provided granular surveillance data and information on their surveillance system. A median of 1,641 (IQR:552 – 2,415) RSV cases per season were reported from 2000 and 2020. The majority (55%) of RSV cases occurred in the <1-year-olds, with 8% of cases reported in those aged ≥65 years. Hospitalized cases were younger than those in community care. We found no age difference between RSV subtypes and no clear pattern of dominant subtypes. Conclusions The high number of cases in the <1 year-olds indicates a need to focus prevention efforts in this group. The minimal differences between RSV subtypes and their co-circulation implies prevention needs to target both subtypes. Importantly, there appears to be a lack of RSV surveillance data in the elderly