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Frontiers in Immunology 2022Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in... (Meta-Analysis)
Meta-Analysis
Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in clinical settings, a meta-analysis of 255 clinical trials was performed. A total of 7,289 patients are planned to be dosed. AAV2 was the most dominantly used serotype (29.8%, n=72), and 8.3% (n=20) of trials used engineered capsids. 38.7% (n=91) of trials employed neutralizing antibody assays for patient enrollment, while 15.3% (n=36) used ELISA-based total antibody assays. However, there was high variability in the eligibility criteria with cut-off tiers ranging from 1:1 to 1:1,600. To address potential immunogenicity, 46.3% (n=118) of trials applied immunosuppressants (prophylactic or reactive), while 32.7% (n=18) of CNS and 37.5% (n=24) of ocular-directed trials employed immunosuppressants, possibly due to the immune-privileged status of CNS and retina. There were a total of 11 patient deaths across 8 trials, and 18 out of 30 clinical holds were due to toxicity findings in clinical studies. 30.6% (n=78) of trials had treatment-emergent serious adverse events (TESAEs), with hepatotoxicity and thrombotic microangiopathy (systemic delivery) and neurotoxicity (CNS delivery) being the most prominent. Additionally, the durability of gene therapy may be impacted by two distinct decline mechanisms: 1) rapid decline presumably due to immune responses; or 2) gradual decline due to vector dilution. The durability varied significantly depending on disease indication, dose, serotypes, and patient individuals. Most CNS (90.0%) and muscle trials (73.3%) achieved durable transgene expression, while only 43.6% of ocular trials had sustained clinical outcomes. The rAAV production system can affect rAAV quality and thus immunogenicity and toxicity. Out of 186 trials that have disclosed production system information, 63.0% (n=126) of trials used the transient transfection of the HEK293/HEK293T system, while 18.0% (n=36) applied the baculovirus/Sf9 (rBac/Sf9) system. There were no significant differences in TESAEs and durability between AAV generated by rBac/Sf9 and HEK293/HEK293T systems. In summary, rAAV immunogenicity and toxicity poses significant challenges for clinical development of rAAV gene therapies, and it warrants collaborative efforts to standardize monitoring/measurement methods, design novel strategies to overcome immune responses, and openly share relevant information.
Topics: Humans; Dependovirus; HEK293 Cells; Genetic Vectors; Genetic Therapy; Immunosuppressive Agents
PubMed: 36389770
DOI: 10.3389/fimmu.2022.1001263 -
Frontiers in Immunology 2022To investigate the efficacy, effectiveness and safety of recombinant zoster vaccine (RZV) and zoster vaccine live (ZVL) in immunocompetent and immunocompromised subjects. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To investigate the efficacy, effectiveness and safety of recombinant zoster vaccine (RZV) and zoster vaccine live (ZVL) in immunocompetent and immunocompromised subjects.
METHODS
Data sources: PubMed, EMBASE, Cochrane Library, and Web of Science databases (up to Jan 2022) were searched to identify English articles. Search terms included randomized controlled trials (RCTs), observational studies, herpes zoster, RZV, ZVL. Study Selection: Only randomized controlled trials (RCTs) evaluating vaccine efficacy and safety and observational studies assessing vaccine effectiveness (after a vaccine was approved for marketing) were included. Data Extraction: Two researchers independently screened the literature, extracted the data, and checked the each other results.
RESULTS
Seventeen RCTs and 19 cohort studies were included. Among immunocompetent subjects, RZV was superior to ZVL at wide intervals (relative vaccine efficacy: 84%, 95% CI: 53%-95%; relative vaccine effectiveness: 49%, 95% CI: 21%-67%), across genders and subjects aged ≥ 60 years. Among immunocompromised subjects, RZV was superior to placebo in terms of vaccine efficacy (60%, 95% CI: 49%-69%). There was no difference between ZVL and placebo in those with selected immunosuppressive conditions. RZV was 45% (95% CI: 30%-59%) superior to ZVL in real-world practice. Compared with placebo, adverse events related to RZV were primarily related to injection-site and systemic, and RZV did not increase the risk of serious adverse events (SAEs) or death. There was no difference in the incidence of adverse events between groups with and without immunosuppression.
CONCLUSIONS
Both RZV and ZVL can reduce the risk of herpes zoster in both immunocompetent and immunocompromised subjects. RZV was well-tolerated in the study population and demonstrated stronger protection than ZVL.
SYSTEMATIC REVIEW REGISTRATION
Prospero CRD42022310495.
Topics: Herpes Zoster; Herpes Zoster Vaccine; Herpesvirus 3, Human; Humans; Network Meta-Analysis; Vaccines, Synthetic
PubMed: 36248796
DOI: 10.3389/fimmu.2022.978203 -
The Lancet. Healthy Longevity Apr 2022Given the substantial impact of herpes zoster on health and quality of life, and its considerable economic burden, prevention through vaccination is a priority. We aimed... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Given the substantial impact of herpes zoster on health and quality of life, and its considerable economic burden, prevention through vaccination is a priority. We aimed to evaluate the effectiveness of the herpes zoster vaccines (recombinant zoster vaccine [RZV] and zoster vaccine live [ZVL]) against incident herpes zoster and postherpetic neuralgia in older adults.
METHODS
We did a systematic review and meta-analysis of studies assessing the effectiveness of herpes zoster vaccines in adults aged 50 years or older, compared with no vaccination or another vaccine. We searched published literature on MEDLINE, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ProQuest Central, and Dimensions, as well as unpublished studies, grey literature, and the reference lists of included studies. Observational studies published in any language between May 25, 2006, and Dec 31, 2020, were included. Eligible studies were appraised for methodological quality using standardised critical appraisal instruments from the Joanna Briggs Institute, and data were extracted from selected studies using a standardised tool. Random-effects meta-analysis models were used to estimate pooled vaccine effectiveness for outcomes of interest (herpes zoster, herpes zoster ophthalmicus, and postherpetic neuralgia) among clinically and methodologically comparable studies, with a fixed-effects model also used for herpes zoster ophthalmicus. Vaccine effectiveness was also assessed in people with comorbidities. As a post-hoc analysis, a forward citation search was done on Jan 31, 2021. This study is registered on PROSPERO, CRD42021232383.
FINDINGS
Our search identified 1240 studies, of which 1162 were excluded based on title and abstract screening. A further 56 articles were excluded on reading the full text. 22 studies (21 cohort studies and one case-control study, involving 9 536 086 participants and 3·35 million person-years in the USA, UK, Canada, and Sweden) were included in the quantitative analysis. Of these, 13 articles were included in the meta-analysis. The overall quality of evidence was very low for all outcomes. The pooled vaccine effectiveness for ZVL against herpes zoster in adults was 45·9% (95% CI 42·2-49·4; seven studies). The vaccine effectiveness for ZVL against postherpetic neuralgia was 59·7% (58·4-89·7; three studies) and against herpes zoster ophthalmicus (in a fixed-effects model) was 30·0% (20·5-38·4; two studies). ZVL was effective in preventing herpes zoster in people with comorbidities, including diabetes (vaccine effectiveness 49·8%, 45·1-54·1; three studies), chronic kidney disease (54·3%, 49·0-59·1; four studies), liver disease (52·9%, 41·6-62·1; two studies), heart disease (52·3%, 45·0-58·7; two studies), and lung disease (49·0%, 32·2-66·2; two studies). In a post-hoc analysis of two studies from the USA published after 2020, the pooled vaccine effectiveness for RZV against herpes zoster in adults was 79·2% (57·6-89·7). Substantial heterogeneity (I≥75%) was observed in 50% of the meta-analyses.
INTERPRETATION
ZVL and RZV are effective in preventing herpes zoster in routine clinical practice. ZVL also reduces the risk of postherpetic neuralgia. Selection bias and confounding by unmeasured variables are inherent challenges of observational studies based on large health-care databases. Nevertheless, these findings will reassure policy makers, health practitioners, and the public that the vaccinations currently available for herpes zoster vaccination programmes are effective at preventing herpes zoster and related complications.
FUNDING
None.
Topics: Aged; Case-Control Studies; Herpes Zoster Ophthalmicus; Herpes Zoster Vaccine; Herpesvirus 3, Human; Humans; Neuralgia, Postherpetic; Quality of Life; Vaccine Efficacy; Vaccines, Synthetic
PubMed: 36098300
DOI: 10.1016/S2666-7568(22)00039-3 -
Vaccine Sep 2022Human papillomavirus (HPV) vaccines were first licensed as a three-dose series. Two doses are now widely recommended in some age groups; there are data suggesting high... (Review)
Review
BACKGROUND
Human papillomavirus (HPV) vaccines were first licensed as a three-dose series. Two doses are now widely recommended in some age groups; there are data suggesting high efficacy with one dose. We updated a systematic literature review of HPV vaccine effectiveness by number of doses in observational studies.
METHODS
We searched Medline and Embase databases from January 1, 2007, through September 29, 2021. Data were extracted and summarized in a narrative synthesis. We also conducted quality assessments for bias due to selection, information, and confounding.
RESULTS
Overall, 35 studies were included; all except one were conducted within the context of a recommended three-dose schedule. Evaluations were in countries that used bivalent HPV vaccine (seven), quadrivalent HPV vaccine (27) or both (one). Nine evaluated effectiveness against HPV infection, ten anogenital warts, and 16 cervical abnormalities. All studies were judged to have moderate or serious risk of bias. The biases rated as serious would likely result in lower effectiveness with fewer doses. Investigators attempted to control for or stratify by potentially important variables, such as age at vaccination. Eight studies evaluated impact of buffer periods (lag time) for case counting and 10 evaluated different intervals between doses for two-dose vaccine recipients. Studies that stratified by vaccination age found higher effectiveness with younger age at vaccination, although differences were not all formally tested. Most studies found highest estimates of effectiveness with three doses; significant effectiveness was found among 28/29 studies that evaluated three doses, 19/29 that evaluated two doses, and 18/30 that evaluated one dose. Some studies that adjusted or stratified analyses by age at vaccination found similar effectiveness with three, two and one doses.
CONCLUSION
Observational studies of HPV vaccine effectiveness have many biases. Studies examining persons vaccinated prior to sexual activity and using methods to reduce sources of bias are needed for valid effectiveness estimates.
Topics: Alphapapillomavirus; Female; Humans; Immunization Programs; Papillomavirus Infections; Papillomavirus Vaccines; Uterine Cervical Neoplasms; Vaccination; Vaccine Efficacy
PubMed: 35965239
DOI: 10.1016/j.vaccine.2022.06.065 -
Sexually Transmitted Diseases Jun 2021No clear guidelines are available for the management of pregnant women with condyloma acuminata, a human papillomavirus-associated benign neoplasm that develops in the...
No clear guidelines are available for the management of pregnant women with condyloma acuminata, a human papillomavirus-associated benign neoplasm that develops in the genital tract. We performed a systematic review to gain a better understanding of the management of condyloma acuminata during pregnancy. In this review, we mainly focused on treatments. We searched PubMed, Google Scholar, and Web of Science to identify studies on the treatment of condyloma acuminata during pregnancy. Thirty articles met the inclusion criteria. The treatment methods described in the literature were laser therapy, cryotherapy, imiquimod, photodynamic therapy, trichloroacetic acid, and local hyperthermia. The most effective treatment remains unclear. Various factors must be considered when deciding how to treat. Based on our assessment of the literature, we recommend cryotherapy as the first-choice treatment and laser therapy as the second-choice treatment. Imiquimod can be considered in cases such as extensive condyloma acuminata that is not easily treated by cryotherapy or laser therapy. In such cases, sufficient informed consent must be obtained from the patient. Cryotherapy, laser therapy, and imiquimod have been administered during all 3 trimesters with no severe adverse effects, but we cautiously recommend reserving laser therapy until the third trimester because of the lower risk of recurrence before delivery. There are still many unclear points regarding the management of condyloma in pregnancy, and further research is needed.
Topics: Condylomata Acuminata; Female; Humans; Imiquimod; Papillomaviridae; Photochemotherapy; Pregnancy; Recurrence
PubMed: 33093288
DOI: 10.1097/OLQ.0000000000001322 -
Nature Reviews. Drug Discovery Mar 2021
Topics: Animals; Dependovirus; Genetic Therapy; Genetic Vectors; Humans
PubMed: 33495615
DOI: 10.1038/d41573-021-00017-7 -
Tropical Medicine & International... Nov 2022On 7th May 2022, human monkeypox was identified in the United Kingdom, a non-endemic zone, with subsequent multi-country outbreaks. About 6 weeks later, the European... (Review)
Review
BACKGROUND
On 7th May 2022, human monkeypox was identified in the United Kingdom, a non-endemic zone, with subsequent multi-country outbreaks. About 6 weeks later, the European Centre for Disease Prevention and Control reported 1158 confirmed cases in non-endemic countries scattered within the European Economic Area (EEA), and a total of 1882 cases confirmed worldwide, inclusive of the EEA. These numbers are expected to increase with high alert and amplified surveillance established in non-endemic regions. In light of a looming epidemic, current understanding of the virus, and identification of gaps in the literature remain critical hence warranting a scoping review of available literature.
METHODS
Literature searches were performed through PubMed, SCOPUS, ScienceDirect and Hinari to identify studies eligible for inclusion in accordance with PRISMA guidelines.
RESULTS
Seventy-seven articles were included in the review. Majority of the cases were from the Central African clade (n = 29,905) versus the West African clade (n = 252). 6/16 articles that reported vaccination status stated that none of the cases were vaccinated. In the remaining articles, approximately 80%-96% cases were unvaccinated. It was noted that 4%-21% of the vaccinated individuals got infected. The secondary attack rate ranged from 0% to 10.2%, while the calculated pooled estimated case fatality rate was 8.7%.
CONCLUSION
This scoping review provides an extensive look at our current understanding on monkeypox disease. Further studies are needed to better understand its risk factors, genetics and natural history, in order for public health strategists to generate prevention strategies and management decisions.
Topics: Humans; Mpox (monkeypox); Monkeypox virus; Disease Outbreaks; Public Health; Epidemics
PubMed: 36229989
DOI: 10.1111/tmi.13821 -
Clinical Infectious Diseases : An... Oct 2020The primary reported risk factors for herpes zoster (HZ) include increasing age and immunodeficiency, yet estimates of HZ risk by immunocompromising condition have not...
BACKGROUND
The primary reported risk factors for herpes zoster (HZ) include increasing age and immunodeficiency, yet estimates of HZ risk by immunocompromising condition have not been well characterized. We undertook a systematic literature review to estimate the HZ risk in immunocompromised patients.
METHODS
We systematically reviewed studies that examined the risk of HZ and associated complications in adult patients with hematopoietic cell transplants (HCT), cancer, human immunodeficiency virus (HIV), and solid organ transplant (SOT). We identified studies in PubMed, Embase, Medline, Cochrane, Scopus, and clinicaltrials.gov that presented original data from the United States and were published after 1992. We assessed the risk of bias with Cochrane or Grading of Recommendations Assessment, Development, and Evaluation methods.
RESULTS
We identified and screened 3765 records and synthesized 34 studies with low or moderate risks of bias. Most studies that were included (32/34) reported at least 1 estimate of the HZ cumulative incidence (range, 0-41%). There were 12 studies that reported HZ incidences that varied widely within and between immunocompromised populations. Incidence estimates ranged from 9 to 92 HZ cases/1000 patient-years and were highest in HCT, followed by hematologic malignancies, SOT, and solid tumor malignancies, and were lowest in people living with HIV. Among 17 HCT studies, the absence of or use of antiviral prophylaxis at <1 year post-transplant was associated with a higher HZ incidence.
CONCLUSIONS
HZ was common among all immunocompromised populations studied, exceeding the expected HZ incidence among immunocompetent adults aged ≥60 years. Better evidence of the incidence of HZ complications and their severity in immunocompromised populations is needed to inform economic and HZ vaccine policies.
Topics: Adult; Herpes Zoster; Herpes Zoster Vaccine; Herpesvirus 3, Human; Humans; Immunocompromised Host; Incidence; Middle Aged; Neuralgia, Postherpetic; United States
PubMed: 31677266
DOI: 10.1093/cid/ciz1090 -
Autonomic Neuroscience : Basic &... Nov 2022Autonomic dysfunction has been occasionally described in varicella-zoster virus (VZV) infection, while few systematic reviews are available. We systematically review... (Review)
Review
BACKGROUND AND PURPOSE
Autonomic dysfunction has been occasionally described in varicella-zoster virus (VZV) infection, while few systematic reviews are available. We systematically review autonomic dysfunction due to VZV infection.
METHODS
This study followed the PRISMA guideline, and three databases were researched and included cross-sectional studies in full-length publications in the English language using appropriate search keywords.
RESULTS
A total of 102 articles were identified initially; finally 45 studies were used for review, comprising pupillomotor dysfunction in 4, sudomotor dysfunction in 2, cardiovascular dysfunction in 2, gastrointestinal dysfunction in 14, and urogenital dysfunction in 23. They can be summarized as (1) VZV infection rarely produces orthostatic hypotension, which involves diffuse sympathetic dysfunction by polyneuropathy. (2) In contrast, VZV infection produces dysfunction of the bladder and the bowel, which involves segmental parasympathetic or sympathetic dysfunction by dorsal root ganglionopathy.
CONCLUSIONS
Awareness of VZV-related autonomic dysfunction is important, because such patients may first visit a gastroenterology or urology clinic. Close collaboration among neurologists, dermatologists, gastroenterologists, and urologists is important to start early antiviral agents and maximize bowel and bladder care in such patients.
Topics: Autonomic Nervous System Diseases; Chickenpox; Cross-Sectional Studies; Herpes Zoster; Herpesvirus 3, Human; Humans
PubMed: 35863181
DOI: 10.1016/j.autneu.2022.103018 -
The Lancet. HIV Sep 2021Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts....
Epidemiology of anal human papillomavirus infection and high-grade squamous intraepithelial lesions in 29 900 men according to HIV status, sexuality, and age: a collaborative pooled analysis of 64 studies.
BACKGROUND
Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts. We aimed to evaluate the age-specific prevalence of anal HPV, HSIL, and their combination, in men, stratified by HIV status and sexuality.
METHODS
We did a systematic review for studies on anal HPV infection in men and a pooled analysis of individual-level data from eligible studies across four groups: HIV-positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive men who have sex with women (MSW), and HIV-negative MSW. Studies were required to inform on type-specific HPV infection (at least HPV16), detected by use of a PCR-based test from anal swabs, HIV status, sexuality (MSM, including those who have sex with men only or also with women, or MSW), and age. Authors of eligible studies with a sample size of 200 participants or more were invited to share deidentified individual-level data on the above four variables. Authors of studies including 40 or more HIV-positive MSW or 40 or more men from Africa (irrespective of HIV status and sexuality) were also invited to share these data. Pooled estimates of anal high-risk HPV (HR-HPV, including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and HSIL or worse (HSIL+), were compared by use of adjusted prevalence ratios (aPRs) from generalised linear models.
FINDINGS
The systematic review identified 93 eligible studies, of which 64 contributed data on 29 900 men to the pooled analysis. Among HIV-negative MSW anal HPV16 prevalence was 1·8% (91 of 5190) and HR-HPV prevalence was 6·9% (345 of 5003); among HIV-positive MSW the prevalences were 8·7% (59 of 682) and 26·9% (179 of 666); among HIV-negative MSM they were 13·7% (1455 of 10 617) and 41·2% (3798 of 9215), and among HIV-positive MSM 28·5% (3819 of 13 411) and 74·3% (8765 of 11 803). In HIV-positive MSM, HPV16 prevalence was 5·6% (two of 36) among those age 15-18 years and 28·8% (141 of 490) among those age 23-24 years (p=0·0091); prevalence was 31·7% (1057 of 3337) among those age 25-34 years and 22·8% (451 of 1979) among those age 55 and older (p<0·0001). HPV16 prevalence in HIV-negative MSM was 6·7% (15 of 223) among those age 15-18 and 13·9% (166 of 1192) among those age 23-24 years (p=0·0076); the prevalence plateaued thereafter (p=0·72). Similar age-specific patterns were observed for HR-HPV. No significant differences for HPV16 or HR-HPV were found by age for either HIV-positive or HIV-negative MSW. HSIL+ detection ranged from 7·5% (12 of 160) to 54·5% (61 of 112) in HIV-positive MSM; after adjustment for heterogeneity, HIV was a significant predictor of HSIL+ (aPR 1·54, 95% CI 1·36-1·73), HPV16-positive HSIL+ (1·66, 1·36-2·03), and HSIL+ in HPV16-positive MSM (1·19, 1·04-1·37). Among HPV16-positive MSM, HSIL+ prevalence increased with age.
INTERPRETATION
High anal HPV prevalence among young HIV-positive and HIV-negative MSM highlights the benefits of gender-neutral HPV vaccination before sexual activity over catch-up vaccination. HIV-positive MSM are a priority for anal cancer screening research and initiatives targeting HPV16-positive HSIL+.
FUNDING
International Agency for Research on Cancer.
Topics: Age Factors; Anal Canal; HIV Infections; Humans; Male; Papillomaviridae; Papillomavirus Infections; Prevalence; Risk Factors; Sexuality; Squamous Intraepithelial Lesions
PubMed: 34339628
DOI: 10.1016/S2352-3018(21)00108-9