Neutralization of non-vaccine human papillomavirus pseudoviruses from the A7 and A9 species groups by bivalent HPV vaccine sera

The majority of cervical cancers are associated with infection by one or more Human Papillomavirus (HPV) types from just two distinct Alpha-Papillomavirus species groups, A7 and A9. The extent to which the current HPV16/18 vaccines will protect against other genetically related HPV types is of interest to inform vaccine implementation, cervical disease surveillance and the development of second generation HPV vaccines. The aim of this study was to determine the frequency and titer of neutralizing antibodies against a range of A7 (18, 39, 45, 59, 68) and A9 (16, 31, 33, 35, 52, 58) HPV types using sera from individuals immunized with the bivalent HPV vaccine within the school-based, UK national HPV immunization programme. Serum samples were collected from 69 girls aged 13-14 years, a median 5.9 months (inter-quartile range, IQR, 5.7-6.0) after their third vaccine dose. Cross-neutralizing antibodies against HPV31, HPV33, HPV35 and HPV45 were common and strongly associated with the titer for the related vaccine-type, but were considerably lower (<1%) than their related vaccine type-specific response. The low prevalence of these HPV types in the population and the ages within the study cohort suggest these responses are due to vaccination. It is unclear whether such low levels of neutralizing antibodies would be sufficient to protect at the site of infection in the absence of other immune effectors but the coincidence with HPV types reported from efficacy studies is intriguing. The utility of neutralizing antibodies as surrogate markers of protection remains to be determined.     

Safety of COVID-19 vaccines during pregnancy: A systematic review and meta-analysis

BackgroundAssessment of COVID-19 vaccines safety during pregnancy is urgently needed.MethodsWe conducted a systematic review and meta-analysis to evaluate the safety of COVID-19 vaccines, including their components and technological platforms used in other vaccines during pregnancy and animal studies to complement direct evidence. We searched literature databases from its inception to September 2021 without language restriction, COVID-19 vaccine websites, and reference lists of other systematic reviews and the included studies. Pairs of reviewers independently selected, data extracted, and assessed the risk of bias of the studies. Discrepancies were resolved by consensus. (PROSPERO CRD42021234185).ResultsWe retrieved 8,837 records from the literature search; 71 studies were included, involving 17,719,495 pregnant persons and 389 pregnant animals. Most studies (94%) were conducted in high-income countries, were cohort studies (51%), and 15% were classified as high risk of bias. We identified nine COVID-19 vaccine studies, seven involving 309,164 pregnant persons, mostly exposed to mRNA vaccines. Among non-COVID-19 vaccines, the most frequent exposures were AS03 and aluminum-based adjuvants.A meta-analysis of studies that adjusted for potential confounders showed no association with adverse outcomes, regardless of the vaccine or the trimester of vaccination.Neither the reported rates of adverse pregnancy outcomes nor reactogenicity exceeded expected background rates, which was the case for ASO3- or aluminum-adjuvanted non-COVID-19 vaccines in the proportion meta-analyses of uncontrolled studies/arms. The only exception was postpartum hemorrhage after COVID-19 vaccination (10.40%; 95% CI: 6.49–15.10%), reported by two studies; however, the comparison with non-exposed pregnant persons, available for one study, found non-statistically significant differences (adjusted OR 1.09; 95% CI 0.56–2.12). Animal studies showed consistent results with studies in pregnant persons.ConclusionWe found no safety concerns for currently administered COVID-19 vaccines during pregnancy. Additional experimental and real-world evidence could enhance vaccination coverage. Robust safety data for non-mRNA-based COVID-19 vaccines are still needed.     

Two-dose schedules for human papillomavirus vaccine: Systematic review and meta-analysis

Simpler schedules for human papillomavirus (HPV) vaccine delivery could improve vaccine coverage and the effectiveness of cervical cancer prevention. The objective of this study was to systematically review evidence about the effects of two-dose compared with three-dose schedules for human papillomavirus (HPV) vaccine and to describe the uptake of two-dose HPV vaccination schedules globally. We searched PubMed, the Cochrane Central Registry of Controlled Trials, trials registers, and manufacturers’ databases from their earliest date to February 2016. We selected randomised controlled trials and controlled clinical trials that directly compared HPV vaccine schedules with two or three doses. We extracted data on immunological and clinical outcomes and used meta-analysis where appropriate. We also described the use of two-dose HPV vaccine schedules globally. We screened 1464 items and included seven eligible noninferiority trials in 11 countries. In randomised comparisons amongst adolescent girls (three trials), geometric mean concentrations (GMC) of antibodies against HPV16 and HPV18 were non-inferior or inconclusive, up to 24 months after a two-dose compared with a three-dose schedule. One trial with a clinical outcome found no persistent HPV infections occurred after either two or three doses. In non-randomised comparisons, GMC were non-inferior or superior in adolescent girls receiving the two-dose schedule compared with women receiving the three-dose schedule for at least 21 months after vaccination. By February 2017, 23 low and middle income and 25 high income countries had adopted a two-dose HPV vaccination schedule. A two-dose HPV vaccine schedule provides satisfactory immunological outcomes in adolescent girls, but uptake globally is limited, particularly in countries with the highest burden of cervical cancer.     

A systematic review of measures used in studies of human papillomavirus (HPV) vaccine acceptability

Background

The recent proliferation of studies describing factors associated with HPV vaccine acceptability could inform health care providers in improving vaccine coverage and support future research. This review examined measures of HPV and HPV-vaccine knowledge, attitudes, beliefs and acceptability, described psychometric characteristics, and provided recommendations about their use.

Methods

A systematic search of Medline, CINAHL, PsychoInfo, and ERIC through May 2008 for English language reports of quantitative data from parents, young adults or adolescents yielded 79 studies.

Results

The majority of studies were cross-sectional surveys (87%), self-administered (67%), conducted before prophylactic vaccines were publicly available (67%) and utilized convenience samples (65%). Most measured knowledge (80%), general attitudes about HPV vaccination (40%), and willingness to vaccinate one's daughter (26%). Two-thirds did not report reliability or validity of measures. The majority did not specify a theoretical framework.

Conclusions

Use of a theoretical framework, consistent labeling of constructs, more rigorous validation of measures, and testing of measures in more diverse samples are needed to yield measurement instruments that will produce findings to guide practitioners in developing successful community and clinical interventions.     

Safety of vaccines used for routine immunization in the United States: An updated systematic review and meta-analysis

BackgroundUnderstanding the safety of vaccines is critical to inform decisions about vaccination. Our objective was to conduct a systematic review of the safety of vaccines recommended for children, adults, and pregnant women in the United States.MethodsWe searched the literature in November 2020 to update a 2014 Agency for Healthcare Research and Quality review by integrating newly available data. Studies of vaccines that used a comparator and reported the presence or absence of key adverse events were eligible. Adhering to Evidence-based Practice Center methodology, we assessed the strength of evidence (SoE) for all evidence statements. The systematic review is registered in PROSPERO (CRD42020180089).ResultsOf 56,603 reviewed citations, 338 studies reported in 518 publications met inclusion criteria. For children, SoE was high for no increased risk of autism following measles, mumps, and rubella (MMR) vaccine. SoE was high for increased risk of febrile seizures with MMR. There was no evidence of increased risk of  intussusception with rotavirus vaccine at the latest follow-up (moderate SoE), nor of diabetes (high SoE). There was no evidence of increased risk or insufficient evidence for key adverse events for newer vaccines such as 9-valent human papillomavirus and meningococcal B vaccines. For adults, there was no evidence of increased risk (varied SoE) or insufficient evidence for key adverse events for the new adjuvanted inactivated influenza vaccine and recombinant adjuvanted zoster vaccine. We found no evidence of increased risk (varied SoE) for key adverse events among pregnant women following tetanus, diphtheria, and acellular pertussis vaccine, including stillbirth (moderate SoE).ConclusionsAcross a large body of research we found few associations of vaccines and serious key adverse events; however, rare events are challenging to study. Any adverse events should be weighed against the protective benefits that vaccines provide.     

Systematic literature review of neutralizing antibody immune responses to non-vaccine targeted high-risk HPV types induced by the bivalent and the quadrivalent vaccines

IntroductionStudies on the cross-protective effect of HPV bivalent and quadrivalent vaccines demonstrated inconsistent findings against additional HPV types covered by the nonavalent vaccine. The objective of this study was to conduct a systematic literature review to assess the consistency and durability of the cross-protective neutralizing antibody immune responses of the currently licensed bivalent and quadrivalent vaccines to non-vaccine HPV types targeted by the nonavalent vaccine (HPV 6, 11, 31, 33, 45, 52, and 58).MethodsPubMed and EMBASE databases were searched from 2008 to 2019 to identify studies reporting antibody/immune response after vaccination with either the bivalent, quadrivalent, or nonavalent vaccine. Key outcomes were seroconversion, seropositivity or geometric mean titers against HPV types 6, 11, 31, 33, 45, 52, and 58.ResultsEighteen publications met inclusion criteria, reporting on 14 interventional and five observational studies. Across all studies, immune responses to non-vaccine high-risk HPV types after bivalent vaccination were higher than baseline or quadrivalent vaccine. Nonavalent vaccine elicited near total seroconversion to HPV types 31, 33, 45, 52, and 58, with seropositivity remaining near 100% up to 24 months post-dose 1. In contrast, bivalent and quadrivalent vaccination resulted in lower seroconversion levels for non-vaccine types, which waned over time.ConclusionsThe cross-protection antibody/immune response among participants having received all three doses of bivalent or quadrivalent vaccine is not comparable to the specific response elicited by HPV vaccine types. Even in cases where a statistically significant cross-reactive immunological response is reported, long-term data on the duration of the response beyond two years are very limited. Further, the lack of a standard for assays limits comparability of results between studies.     

Factors associated with HPV vaccine uptake in teenage girls: a systematic review

Background

Since 2006 Human papillomavirus (HPV) vaccination has become available to adolescent girls and women in an increasing number of countries, to protect against the virus causing cervical cancer. The vaccine series is offered in three doses over 6 months, and this study aimed to identify factors associated with initiation and/or completion of the 3 dose series in (pre-) adolescent girls. Previous studies have considered intention to vaccinate rather than actual vaccination uptake.

Methods

A systematic search of Medline, Medline in process, Embase and CINAHL, from 2006 to March 2011 for articles related to HPV-vaccine uptake among adolescent girls and factors potentially associated with uptake yielded 25 studies.

Results

The majority of studies were surveys or retrospective reviews of data, only 5 studies reported data on program completion. Most were conducted in the United States (20/25). Higher vaccine uptake was associated with having health insurance, of older age, receipt of childhood vaccines, a higher vaccine related knowledge, more healthcare utilization, having a healthcare provider as a source of information and positive vaccine attitudes. In US settings, African American girls were less likely to have either initiated or completed the three dose vaccination series.

Conclusions

HPV vaccination programs should focus on narrowing disparities in vaccine receipt in ethnic and racial groups and on providing correct information by a reliable source, e.g. healthcare providers. School-based vaccination programs have a high vaccine uptake. More studies are required to determine actual vaccine course completion and factors related to high uptake and completion, and information from a broader range of developed and developing settings is needed.     

Evaluation of serological assays to monitor antibody responses to single-dose HPV vaccines

IntroductionWhether existing serological assays are sufficiently robust to measure the lower antibody levels expected following single-dose HPV vaccination is unknown.MethodsWe evaluated seven assays measuring HPV-16/18 immunological responses overall and by number of doses in 530 serum samples from participants receiving varying doses of Cervarix or Gardasil up to 36-months post-vaccination. Serum was evaluated by simplex (HPV-16 ELISA, HPV-18 ELISA), multiplex (LIA-4, VLP-MIA, M9ELISA, GST-L1), and high-throughput pseudovirion-based neutralization assays (HT-PBNA), and results were compared to the gold standard HPV-16/18 secreted alkaline phosphatase neutralization assay (SEAP-NA). Reproducibility was assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Percent agreement, Pearson correlation, and weighted-kappa were used to assess validity. Determinants of seronegativity were evaluated by chi-squared test.ResultsHPV-16: Seropositivity range was 97.1–99.5% for single dose and 98.8–99.8% overall. CV range was 4.0–18.0% for single dose and 2.9–19.5% overall. ICC range was 0.77–0.99 for single dose and 0.74–0.99 overall. Correlation with SEAP-NA range was 0.43–0.85 for single dose and 0.51–0.90 overall. Weighted-kappa range was 0.34–0.82 for single dose and 0.45–0.84 overall. HPV-18: Seropositivity range was 63.9–94.7% for single dose and 86.2–97.9% overall. CV range was 8.1–18.2% for single dose and 4.6–18.6% overall. ICC range was 0.75–0.99 for single dose and 0.83–0.99 overall. Correlation with SEAP-NA range was 0.31–0.99 for single dose and 0.27–0.96 overall. Weighted-kappa range was 0.35–0.83 for single dose and 0.45–0.84 overall. HPV-16 seronegativity was <5% for all assays. HPV-18 seronegativity range was 5.5–17.3%. For LIA-4 and GST-L1 where the proportion of seronegativity was >10%, the strongest correlates of seronegativity were receiving a single vaccine dose and receiving Gardasil.Conclusions:These results support the utility of existing serological assays to monitor antibody responses following single-dose HPV vaccination.     

Durability of the neutralizing antibody response to vaccine and non-vaccine HPV types 7 years following immunization with either Cervarix® or Gardasil® vaccine

Bivalent (Cervarix®) and quadrivalent (Gardasil®) Human Papillomavirus (HPV) vaccines demonstrate remarkable efficacy against the targeted genotypes, HPV16 and HPV18, but also a degree of cross-protection against non-vaccine incorporated genotypes, HPV31 and HPV45. These outcomes seem to be supported by observations that the HPV vaccines induce high titer neutralizing antibodies against vaccine types and lower responses against non-vaccine types. Few data are available on the robustness of the immune response against non-vaccine types. We examined the durability of vaccine and non-vaccine antibody responses in a follow up of a head-to-head study of 12–15?year old girls initially randomized to receive three doses of Cervarix® or Gardasil® vaccine. Neutralizing antibodies against both vaccine and non-vaccine types remained detectable up to 7?years following initial vaccination and a mixed effects model was used to predict the decline in antibody titers over a 15?year period. The decline in vaccine and non-vaccine type neutralizing antibody titers over the study period was estimated to be 30% every 5–7?years, with Cervarix® antibody titers expected to remain 3–4 fold higher than Gardasil® antibody titers over the long term. The antibody decline rates in those with an initial response to non-vaccine types were similar to that of vaccine types and are predicted to remain detectable for many years. Empirical data on the breadth, magnitude, specificity and durability of the immune response elicited by the HPV vaccines contribute to improving the evidence base supporting this important public health intervention. Original trial: ClinicalTrials.gov NCT00956553.     

Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection.     

Kinetic and HPV infection effects on cross-type neutralizing antibody and avidity responses induced by Cervarix

Background

We previously demonstrated that Cervarix^® elicits antibody responses against vaccine-related types for which clinical efficacy was demonstrated (HPV-31 and -45). Here, we evaluated the kinetics of neutralization titers and avidity of Cervarix^®-induced antibodies up to 36 months of follow-up in unexposed and HPV infected women.

Methods

A subset of women who participated in the Cost Rica HPV-16/18 Vaccine Trial had pre- and post-vaccination sera tested for antibody responses to HPV-16, -18, -31, -45, and -58 using a pseudovirion-based neutralization assay, and HPV-16 antibody avidity using an HPV-16 L1 VLP (virus-like particle)-based ELISA developed in our laboratory.

Results

In uninfected women, neutralizing antibody titers did not reach significance until after the 3rd dose for HPV-31 (month 12, p = 0.009) and HPV-45 (month 12, p = 0.003), but then persisted up to month 36 (HPV-31, p = 0.01; HPV-45, p = 0.002). Individuals infected with HPV-16 or HPV-31 at enrollment developed a significantly higher median antibody response to the corresponding HPV type after one dose, but there was not a difference between median titers after three doses compared to the HPV negative group. Median HPV-16 antibody avidity and titer increased over time up to month 12; however, the HPV-16 avidity did not correlate well with HPV-16 neutralizing antibody titers at each time point examined, except for month 6. The median avidity levels were higher in HPV-16 infected women at month 1 (p = 0.04) and lower in HPV-16 infected women at month 12 (p = 0.006) compared to the HPV negative women.

Conclusions

The persistence of cross-neutralization titers at month 36 suggests cross-reactive antibody responses are likely to persist long-term and are not influenced by infection status at enrollment. However, the weak correlation between avidity and neutralization titers emphasizes the need for examining avidity in efficacy studies to determine if high avidity antibodies play a critical role in protection against infection.     

Influenza vaccine effectiveness against influenza-associated hospitalization in children: A systematic review and meta-analysis

Vaccination remains the most effective way to prevent influenza infection, albeit vaccine effectiveness (VE) varies by year. Compared to other age groups, children and elderly adults have the highest risk of developing influenza-related complications and requiring hospitalization. During the last years, “test negative design” (TND) studies have been implemented in order to estimate influenza VE. The aim of this systematic review and meta-analysis was to summarize the findings of TND studies reporting influenza VE against laboratory-confirmed influenza-related hospitalization in children aged 6 months to 17 years. We searched the PubMed and Embase databases and identified 2615 non-duplicate studies that required detailed review. Among them, 28 met our inclusion criteria and we performed a random-effects meta-analysis using adjusted VE estimates. In our primary analysis, influenza vaccine offered significant protection against any type influenza-related hospitalization (57.48%; 95% CI 49.46–65.49). When we examined influenza VE per type and strain, VE was higher against H1N1 (74.07%; 95% CI: 54.85–93.30) and influenza B (50.87%; 95% CI: 41.75–59.98), and moderate against H3N2 (40.77%; 95% CI: 25.65–55.89). Notably, influenza vaccination offered higher protection in children who were fully vaccinated (61.79%; 95% CI: 54.45–69.13), compared to those who were partially vaccinated (33.91%; 95% CI: 21.12 – 46.69). Also, influenza VE was high in children less than 5 years old (61.71%; 95% CI: 49.29–74.12) as well as in children 6–17 years old (54.37%; 95% CI: 35.14–73.60). In conclusion, in the pediatric population, influenza vaccination offered significant protection against influenza-related hospitalization and complete annual vaccination should be encouraged.     

Global economic evaluations of rotavirus vaccines: A systematic review

Introduction: World Health Organization (WHO) recommends Rotavirus vaccines to prevent and control rotavirus infections. Economic evaluations (EE) have been considered to support decision making of national policy. Summarizing global experience of the economic value of rotavirus vaccines is crucial in order to encourage global WHO recommendations for vaccine uptake. Therefore, a systematic review of economic evaluations of rotavirus vaccine was conducted.Methods: We searched Medline, Embase, NHS EED, EconLit, CEA Registry, SciELO, LILACS, CABI-Global Health Database, Popline, World Bank - e-Library, and WHOLIS. Full economic evaluations studies, published from inception to November 2015, evaluating Rotavirus vaccines preventing Rotavirus infections were included. The methods, assumptions, results and conclusions of the included studies were extracted and appraised using WHO guide for standardization of EE of immunization programs.Results: 104 relevant studies were included. The majority of studies were conducted in high-income countries. Cost-utility analysis was mostly reported in many studies using incremental cost-effectiveness ratio per DALY averted or QALY gained. Incremental cost per QALY gained was used in many studies from high-income countries. Mass routine vaccination against rotavirus provided the ICERs ranging from cost-saving to highly cost-effective in comparison to no vaccination among low-income countries. Among middle-income countries, vaccination offered the ICERs ranging from cost-saving to cost-effective. Due to low- or no subsidized price of rotavirus vaccines from external funders, being not cost-effective was reported in some high-income settings.Conclusion: Mass vaccination against rotavirus was generally found to be cost-effective, particularly in low- and middle-income settings according to the external subsidization of vaccine price. On the other hand, it may not be a cost-effective intervention at market price in some high-income settings. This systematic review provides supporting information to health policy-makers and health professionals when considering rotavirus vaccination as a national program.     

Does consecutive influenza vaccination reduce protection against influenza: A systematic review and meta-analysis

IntroductionVaccination against influenza on an annual basis is widely recommended, yet recent studies suggest consecutive vaccination may reduce vaccine effectiveness (VE).PurposeTo assess whether when examining the entirety of existing data consecutive influenza vaccination reduces VE compared to current season influenza vaccination.Data sourcesMEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 26, 2017; citations of included studies.Study selectionRandomized, controlled trials (RCTs) and observational studies of children, adults and/or the elderly that reported laboratory-confirmed influenza infection over 2 or more consecutive influenza seasons were eligible.Data extractionData related to study characteristics, participant demographics, cases of influenza infection by vaccination group and risk of bias assessment was extracted in duplicate.Data synthesisFive RCTs involving 11,987 participants did not show a significant reduction in VE when participants vaccinated in two consecutive seasons (VE 71%, 95% CI 62–78%) were compared to those vaccinated in the current season (VE 58%, 95% CI 48–66%) (odds ratio [OR] 0.88, 95% CI 0.62–1.26, p = 0.49, I² = 39%). Twenty-eight observational studies involving 28,627 participants also did not show a reduction (VE for two consecutive seasons 41%, 95% CI 30–51% compared to VE for current season 47%, 95% CI 39–54%; OR 1.14, 95% CI 0.98–1.32, p = 0.09, I² = 63%). Results from subgroup analyses by influenza type/subtype, vaccine type, age, vaccine match and co-morbidity support these findings; however, dose–response results were inconsistent. Certainty in the evidence was assessed to be very low due to unexplained heterogeneity and imprecision.LimitationsThe inclusion of studies with relatively small sample sizes and low event rates contributed to the imprecision of summary VE and OR estimates, which were based on unadjusted data.ConclusionAvailable evidence does not support a reduction in VE with consecutive influenza vaccination, but the possibility of reduced effectiveness cannot be ruled out due to very low certainty in this evidence.Funding sourceCIHR Foundation Grant (PROSPERO: CRD42017059893).     

Therapeutic human papillomavirus vaccines in head and neck cancer: A systematic review of current clinical trials

ObjectivesThis systematic review provides an overview of the current clinical trials investigating therapeutic vaccines for HPV+ head and neck cancer and discusses the future directions of therapeutic vaccine therapy.Materials and methodsA systematic search was conducted in PubMed, EMBASE, Cochrane and clinicaltrials.gov for clinical trials involving therapeutic vaccines. We included studies initiated between 2000 and 2018 with patients diagnosed with HPV+ head and neck cancer and extracted data concerning type of vaccine therapy, adverse events, immunogenicity and clinical outcome measures (e.g. tumour response, progression-free survival and overall survival).ResultsWe identified 11 studies (n = 376 patients) initiated between year 2005 and 2017. Four studies (n = 34) presented preliminary results in patients with incurable, recurrent loco-regional or distant metastatic disease indicating a positive immune response with 74% (n = 25/34 patients) having elevated antibody levels, IFN-γ and/or T-cell response. Five studies presented data on the vaccines’ safety profile, demonstrating predominantly grade 1 and 2 toxicity. Three studies evaluated the clinical outcome – one study showed no complete or partial response, one study demonstrated stable disease as the best tumour response in 64% (n = 9/14 patients) and one study showed a 33% overall response rate: one patient with a complete response and seven patients with a partial response.ConclusionsTreatment with therapeutic vaccines is a promising and seemingly safe strategy for patients with HPV+ head and neck cancer. However, there are not enough data to draw any further conclusions and clinical outcome measures and tumour responses to the vaccines are still missing.     

Systematic review of cost-effectiveness studies of human papillomavirus (HPV) vaccination: 9-Valent vaccine,gender-neutral and multiple age cohort vaccination

BackgroundThe success of human papillomavirus (HPV) national immunization program depends on effective strategies in optimizing the uptake of HPV vaccine. Given the increasing number of economic evaluations, this review was conducted to update the economic evidence on HPV vaccination, by focusing on: (i) 9-valent vaccine compared to bi- or quadrivalent vaccine; (ii) gender-neutral vaccination compared to female only vaccination; and (iii) multiple age cohort immunization compared to single age cohort immunization.MethodsSearches were performed until June 2016 using 4 databases: PubMed; Embase; Cochrane Library; and LILACS. The combined WHO, Drummond and CHEERS checklist were used to evaluate the quality of included studies.ResultsThirty-four studies were included in the review and most of them were conducted in high-income countries. The inclusion of adolescent boys in vaccination program was found to be cost-effective if vaccine price and coverage was low. When coverage for female was above 75%, gender-neutral vaccination was less cost-effective than when targeting only girls aged 9–18 years. Current evidence does not show conclusive proof of greater cost-effectiveness of 9-valent vaccine compared to the older HPV vaccines as the price for 9-valent vaccine was still uncertain. Multicohort immunization strategy was cost-effective in the age range 9–14 years but the upper age limit at which vaccination was no longer cost-effective needs to be further investigated. Key influential parameters identified were duration of vaccine protection, vaccine price, coverage, and discounting rates.ConclusionsThese findings are expected to support policy-makers in making recommendations for HPV immunization programs on either switching to the 9-valent vaccine or inclusion of adolescent boys’ vaccination or extending the age of vaccination.     

Immunoprophylaxis pharmacotherapy against canine leishmaniosis: A systematic review and meta-analysis on the efficacy of vaccines approved in European Union

Leishmania (L.) infantum is a vector-borne parasite currently endemic in several Southern countries of European Union (EU), and dogs represent the main reservoir and hosts. Data from clinical trials are inconsistent with respect to the efficacy of vaccination against L. infantum infection. Therefore, a quantitative synthesis via pairwise meta-analysis was performed in agreement with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) to increase the strength of evidence and assess the real efficacy profile of vaccines against L. infantum currently approved in EU. Data obtained from 1,394 dogs were extracted from 10 studies. The overall analysis indicated that vaccination is significantly effective in protecting against L. infantum infection (RR 0.40, 95%CI 0.23–0.72; I² 70%; P < 0.01 vs. negative controls). The subset analysis performed by excluding the effect modifiers and by considering only the studies that assessed the efficacy of vaccines currently available in EU, indicated that CaniLeish® (RR 0.38, 95%CI 0.20–0.72; I² 0%), but not Letifend® (RR 0.43, 95%CI 0.15–1.22; I² 37%), significantly protected against L. infantum infection when compared to negative controls (P < 0.05). The number needed to treat analysis showed that 3.77 (95%CI 2.59–6.94) and 10.99 (95%CI 8.28–16.34) dogs had to be treated with CaniLeish® and Letifend®, respectively, to prevent one case of infection compared to negative controls. Vaccination is effective in protecting against the risk L. infantum infection, but further studies are needed to assess whether CaniLeish® and Letifend® are characterized by similar efficacy profile.     

Air pollution and Parkinson's disease: A systematic review and meta-analysis up to 2018

BackgroundRecent epidemiological findings investigate effects of exposure to air pollution on neurodegenerative disease. We performed a systematic review and meta-analysis to investigate the association between air pollution exposure and Parkinson's disease (PD).MethodsWe performed an extensive literature search in PubMed and Google Scholar databases and further searched for unpublished results in conference abstracts until November 2018. We identified 102 unique studies referring to air pollution and PD, from which 15 were included in the meta-analyses. We applied random-effects models to combine risk estimates and investigated between studies heterogeneity. We assessed publication bias through plots and the Egger's test in cases of sufficient number of studies. We assessed associations accounting for multi-pollutant exposures and effect modification patterns by sex and smoking habits.ResultsWe identified 13 reports investigating associations of PD with long-term exposure to regulated air pollutants whilst two reported associations for short-term exposure to PM_2.5. The pooled relative risk (RR) for incidence of PD following an increase in long-term exposure for 10 μg/m³ in PM_2.5 was 1.06 (95% Confidence Interval (CI): 0.99, 1.14) and in NO₂ 1.01 (95%CI: 0.98, 1.03), while for 5 ppb increase in O₃ 1.01 (95% CI: 1.00, 1.02) and for 1 mg/m³ in CO 1.34 (95% CI: 0.85, 2.10); the pooled RR for a hospital admission due to PD after a 10 μg/m³ increase in PM_2.5 short-term exposure was 1.03 (95% CI: 1.01, 1.05). There was high heterogeneity between study-specific results for most of the analyses, attributed to different populations under study. Effects were robust to multi-pollutant adjustment while there were indications of higher particles’ effects among non smokers.ConclusionsWe found weak evidence for an association between air pollution, mostly originating from traffic, and PD. Although meta-analysis increases power to detect small associations in rare outcomes, further research is needed to elaborate our suggestive associations. Such results are of public health significance since population aging in developed countries is expected to increase incidence of PD.