Trivalent and quadrivalent seasonal influenza vaccine in adults aged 60 and older: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of influenza vaccines of any valency for adults 60 years and older. DESIGN AND SETTING: Systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs). MEDLINE, EMBASE, JBI Evidence-Based Practice (EBP) Database, PsycINFO, and Cochrane Evidence -Based Medicine database were searched from inception to 20 June 20, 2022. Two reviewers screened, abstracted, and appraised articles (Cochrane Risk of Bias (ROB) 2.0 tool) independently. We assessed certainty of findings using Confidence in Network Meta-Analysis and Grading of Recommendations, Assessment, Development and Evaluations approaches. We performed random-effects meta-analysis and network meta-analysis (NMA), and estimated odds ratios (ORs) for dichotomous outcomes and incidence rate ratios (IRRs) for count outcomes along with their corresponding 95% confidence intervals (CIs) and prediction intervals. PARTICIPANTS: Older adults (≥60 years old) receiving an influenza vaccine licensed in Canada or the USA (vs placebo, no vaccine, or any other licensed vaccine), at any dose. MAIN OUTCOME MEASURES: Laboratory-confirmed influenza (LCI) and influenza-like illness (ILI). Secondary outcomes were the number of vascular adverse events, hospitalisation for acute respiratory infection (ARI) and ILI, inpatient hospitalisation, emergency room (ER) visit for ILI, outpatient visit, and mortality, among others. RESULTS: We included 41 RCTs and 15 companion reports comprising 8 vaccine types and 206 032 participants. Vaccines may prevent LCI compared with placebo, with high-dose trivalent inactivated influenza vaccine (IIV3-HD) (NMA: 9 RCTs, 52 202 participants, OR 0.23, 95% confidence interval (CI) (0.11 to 0.51), low certainty of evidence) and recombinant influenza vaccine (RIV) (OR 0.25, 95%CI (0.08 to 0.73), low certainty of evidence) among the most efficacious vaccines. Standard dose trivalent IIV3 (IIV3-SD) may prevent ILI compared with placebo, but the result was imprecise (meta-analysis: 2 RCTs, 854 participants, OR 0.39, 95%CI (0.15 to 1.02), low certainty of evidence). Any HD was associated with prevention of ILI compared with placebo (NMA: 9 RCTs, 65 658 participants, OR 0.38, 95%CI (0.15 to 0.93)). Adjuvanted quadrivalent IIV (IIV4-Adj) may be associated with the least vascular adverse events, but the results were very uncertain (NMA: eight 8 RCTs, 57 677 participants, IRR 0.18, 95%CI (0.07 to 0.43), very low certainty of evidence). RIV on all-cause mortality may be comparable to placebo (NMA: 20 RCTs, 140 577 participants, OR 1.01, 95%CI (0.23 to 4.49), low certainty of evidence). CONCLUSIONS: This systematic review demonstrated efficacy associated with IIV3-HD and RIV vaccines in protecting older persons against LCI. RIV vaccine may reduce all-cause mortality when compared with other vaccines, but the evidence is uncertain. Differences in efficacy between influenza vaccines remain uncertain with very low to moderate certainty of evidence. PROSPERO REGISTRATION NUMBER: CRD42020177357.

Burden of disease of respiratory syncytial virus in infants, young children and pregnant women and people.

Background: Passive immunization products for infants and pregnant women and people have sparked interest in understanding Canada's respiratory syncytial virus (RSV) burden. This rapid review examines RSV burden of disease in infants, young children and pregnant women and people. Methods: Electronic databases were searched to identify studies and systematic reviews reporting data on outpatient visits, hospitalizations, intensive care unit admissions, deaths and preterm labour associated with RSV. We also contacted Canadian respiratory virus surveillance experts for additional data. Results: Overall, 17 studies on infants and young children and 10 studies on pregnant women and people were included, in addition to primary surveillance data from one Canadian territory (Yukon). There were higher rates of medical utilization for infants than older children. Hospitalization rates were highest in infants under six months (more than 1% annually), with 5% needing intensive care unit admission, but mortality was low. Severe outcomes often occurred in healthy full-term infants and burden was higher than influenza. Respiratory syncytial virus attack rate was 10%-13% among pregnant women and people. Only one study found a higher hospitalization rate in pregnant women and people compared to non-pregnant women and people. Limited evidence was found on intensive care unit admission, death and preterm birth for pregnant women and people. Conclusion: While risk of severe outcomes is larger in high-risk infants and children, healthcare burden is greatest in healthy term infants. The RSV severity for pregnant women and people appears to be similar to that for non-pregnant women and people.

Intraseasonal waning immunity of seasonal influenza vaccine - A systematic review and meta-analysis.

BACKGROUND: Recently, studies have suggested that influenza antibody titers decline with time since vaccination. Duration of vaccine protection is an important factor to determine the optimal timing of vaccination. OBJECTIVE: We aimed to systematically evaluate the implication of waning immunity on the duration of seasonal influenza vaccine antibody response. METHOD: Electronic databases and clinical trial registries were systematically searched to identify phase III/IV randomized clinical trials evaluating the immunogenicity of seasonal influenza vaccines measured by hemagglutination inhibition assay in healthy individuals six months of age and older. Meta-analyses were conducted to compare adjuvanted and standard influenza vaccine responses with time since vaccination. RESULTS: 1918 articles were identified, of which ten were included in qualitative synthesis and seven in quantitative analysis (children; n=3, older adults; n=4). All studies were deemed to be at low risk of bias, except one study deemed at high risk of bias due to missing outcome data. The majority of included studies found a rise in antibody titers at one-month followed by a decline at six-month post-vaccination. At six-months post-vaccination overall risk differences in seroprotection were significantly higher for children vaccinated with adjuvanted compared to standard vaccines (0.29; 95 % confidence interval (CI), 0.14-0.44). A small increase in seroprotection levels was observed among older adults vaccinated with an adjuvanted compared to standard vaccines, which remained constant over six-months (pre-vaccination: 0.03; 95 % CI, 0.00-0.09 and one- and six-months post-vaccination: 0.05; 95 % CI, 0.01-0.09). CONCLUSIONS: Our results found evidence of persistent antibody responses following influenza vaccination over the course of a typical influenza season. Even if influenza vaccine responses wane over a six-month period, vaccination likely still provides a significant advantage in protection, which may be enhanced with adjuvanted vaccines, particularly in children. Further research is needed to identify the exact timing when the decline in antibody response begins to better inform the optimal timing of influenza vaccination programs. TRIAL REGISTRATION: PROSPERO (CRD42019138585).

Summary of the National Advisory Committee on Immunization (NACI) Statement-Recommendations on Fractional Influenza Vaccine Dosing in the Event of a Shortage: Pandemic preparedness.

Background: At the commencement of a pandemic, it is important to consider the impact of respiratory infections on the health system and the possibility of vaccine shortages due to increased demand. In the event of an influenza vaccine shortage, a strategy for administration of fractional influenza vaccine doses might be considered. This article reviews the available evidence for efficacy, effectiveness, immunogenicity and safety of fractional influenza vaccine dosing, and summarizes the National Advisory Committee on Immunization (NACI) recommendations on fractional dosing strategies by public health programs in Canada. Methods: Two rapid literature reviews were undertaken to evaluate the efficacy, effectiveness, immunogenicity and safety of fractional influenza vaccine dosing via the intramuscular or intradermal route. The NACI evidence-based process was used to assess the quality of eligible studies, summarize and analyze the findings, and apply an ethics, equity, feasibility and acceptability lens to develop recommendations. Results: There was limited evidence for the effectiveness of fractional influenza vaccine dosing. Fractional dosing studies were primarily conducted in healthy individuals, mainly young children and infants, with no underlying chronic conditions. There was fair evidence for immunogenicity and safety. Feasibility issues were identified with intradermal use in particular. Conclusion: NACI recommended that, in the event of a significant population-level shortage of influenza vaccine, a full-dose influenza vaccine should continue to be used, and existing vaccine supply should be prioritized for those considered to be at high risk or capable of transmitting to those at high risk of influenza-related complications or hospitalizations. NACI recommended against the use of fractional doses of influenza vaccine in any population.

Evaluation of the 2018-2019 vaccine effectiveness against medically attended influenza-like illness using medical records and claims data.

BACKGROUND: Healthcare administrative databases are a rich source of information that could be leveraged to estimate real-world influenza vaccine effectiveness (VE). We aimed to evaluate the VE of standard egg-based influenza vaccines and determine if administrative healthcare data provide accurate VE estimates compared to the US CDC data. METHODS: This retrospective cohort study was conducted during the 2018-2019 influenza season. Individuals who had at least one relevant record per year between 2015 and 2019 in their electronic medical record were included. Individuals were considered protected 14 days after receiving an influenza vaccine. The outcome was the occurrence of medically attended influenza-like illness (MA-ILI) defined by clinical diagnostic codes. Adjusted odds ratios (aORs) were derived from multivariate logistic regression and adjusted VE (aVEs) were calculated using 100 × (1-aORs). RESULTS: A total of 5,066,980 individuals were included in the analysis with 1,307,702 (25.8%) considered vaccinated. Overall, the median age was 54 (IQR, 32-66) and 58.1% were female. Vaccine protection against MA-ILI was moderate in children and low in adults. All estimates were lower than VEs reported by the CDC for the 2018-2019 influenza season. Our results were robust to potential loss to follow up, but misclassification bias and residual confounding led to underestimation of the 2018-2019 aVE. When stratified by the number of primary care visits, aVE estimates and vaccination coverage increased with the number of primary care visits, reaching estimates similar to those obtained by the US CDC and US national vaccination coverage among those with ≥ 6 primary care visits, resulting in significant positive vaccine protection in frequent healthcare users. CONCLUSIONS: Moderate and low aVEs were observed during the 2018-2019 season using administrative healthcare data, which was likely due to detection and misclassification biases, correlated with healthcare seeking behaviour, leading to an underestimation of the 2018-2019 influenza VE.

Evaluation of influenza case definitions for use in real-world evidence research.

Background: Laboratory confirmation of influenza is not routinely done in practice. With the advent of big data, it is tempting to use healthcare administrative databases for influenza vaccine effectiveness studies, which often rely on clinical diagnosis codes. The objective of this article is to compare influenza incidence curves using international case definitions derived from clinical diagnostic codes with influenza surveillance data from the United States (US) Centers for Disease Control and Prevention (CDC). Methods: This case series describes influenza incidence by CDC week, defined using International Classification of Disease diagnostic codes over four influenza seasons (2015-2016 to 2018-2019) in a cohort of US individuals three years of age and older who consulted at least once per year between 2015 and 2019. Results were compared to the number of influenza-positive specimens or outpatient visits for influenza-like illness obtained from the CDC flu surveillance data. Results: The incidence curves of influenza-related medical encounters were very similar to the CDC's surveillance data for laboratory-confirmed influenza. Conversely, the number of influenza-like illness encounters was high when influenza viruses started to circulate, leading to a discrepancy with CDC-reported data. Conclusion: A specific case definition should be prioritized when data for laboratory-confirmed influenza are not available, as a broader case definition would conservatively bias influenza vaccine effectiveness toward the null.

Effect of early measles vaccination on long-term protection: A systematic review.

BACKGROUND: In North America, the first dose of a measles-containing vaccine (MCV1) is administered at ≥12 months of age. However, MCV1 may be given to infants <12 months living in highly endemic areas or traveling to these areas. Although an early dose of MCV1 leads to immediate protection, it remains unclear how this impacts long-term immunity. METHODS: This systematic review and meta-analysis evaluates the impact of MCV1 given at <12 months vs. ≥12 months of age on long-term immunogenicity and vaccine effectiveness, with long-term defined as at least one-year post-vaccination. PubMed, EMBASE, Global Health, Web of Science and Scopus were searched on October 31st, 2019. Studies were included if they included a cohort of infants vaccinated <12 months of age and evaluated long-term immunogenicity, vaccine efficacy, or effectiveness. RESULTS: A total of 51 texts were identified: 23 reported outcomes related to vaccine effectiveness and 30 to immunogenicity. Infants vaccinated with MCV1 < 12 months of age showed an overall higher risk of measles compared to ≥12 months of age (RR = 3.16, 95% CI: 2.00, 5.01; OR = 2.46, 95% CI: 1.40, 4.32). Risk of measles decreased with increasing age at first vaccination, with those vaccinated with one dose ≥15 months at a lesser risk compared to 12-14 months or <12 months. Measles seroconversion and seropositivity was not affected by age at first vaccination, but antibody levels were significantly lower in the MCV1 < 12-month group (MD = -0.40, 95% CI: -0.71, -0.09). CONCLUSION: Long-term measles seroconversion and seropositivity did not appear to be affected by age at MCV1, while vaccine effectiveness decreased with younger age. There was not enough evidence to look at the effect of age at MCV1 on immune blunting.

Is there a difference in the immune response, efficacy, effectiveness and safety of seasonal influenza vaccine in males and females? - A systematic review.

INTRODUCTION: Seasonal influenza is an important cause of morbidity and mortality, despite being vaccine-preventable. Sex factors (genes and hormones) seem to impact individuals' susceptibility to infectious diseases and their response to vaccination. However, most vaccine studies do not explicitly assess sex differences in vaccine response, but rather adjust for sex. METHODS: We conducted a systematic review to analyze immunogenicity, efficacy, effectiveness and/or safety of seasonal influenza vaccine data stratified by sex. We searched PubMed, EMBASE, CINAHL, Web of Science and clinicaltrials.gov for observational studies and phase III/IV trials from January 1990 to June 2018, published in English or French. Two reviewers independently screened all references, then proceeded to data extraction and quality assessment using the Cochrane tools (RoB and ROBINS-I) on included studies. RESULTS: Of the 5,745 citations retrieved, 46 studies were included in the SR. Overall, 18 studies assessed immunogenicity, 1 estimated efficacy, 6 measured effectiveness and 25 evaluated safety of seasonal influenza vaccine in females and males (four studies reported on two sex-stratified outcomes concomitantly). CONCLUSION: No clear conclusion could be drawn regarding the effect of sex on the immunogenicity and effectiveness of seasonal influenza vaccine, but higher rates of adverse events following immunization (AEFIs) were reported in females. The heterogeneity of data and studies' low quality prevented us from conducting a meta-analysis. There is a need to emphasize on the appropriate use of the terms sex and gender in biomedical research. Evidence of higher quality is needed to better understand sex differences in response to influenza vaccine.

Multiplex Polymerase Chain Reaction Panel for Suspected Pertussis: What About a Positive Mycoplasma pneumoniae Result?

BACKGROUND: The use of bacterial multiplex polymerase chain reaction (PCR) in children with suspected pertussis sometimes yields unexpected positive results for Mycoplasma pneumoniae. We aimed to evaluate the clinical significance of positive M. pneumoniae results in this population. METHODS: Retrospective cohort of consecutive patients with suspected pertussis tested with a bacterial multiplex PCR (including Bordetella pertussis and M. pneumoniae) between June 2015 and March 2017. Medical records were reviewed to compare demographics, clinical presentations and outcomes of patients positive for M. pneumoniae with those positive for B. pertussis and those with negative results, using multivariable logistic regression. RESULTS: A total of 1244 patients were included as follows: 56 (4.5%) with M. pneumoniae, 116 (9.3%) with B. pertussis and 1029 (82.7%) with negative results. Mean age was respectively 4.8 years, 6.5 years and 2.8 years (P < 0.05). Children with M. pneumoniae were less likely to present with cardinal symptoms of pertussis such as paroxysmal cough [adjusted odds ratio (OR): 0.19, 95% confidence interval (CI): 0.08-0.40) but were more likely to have fever (adjusted OR: 10.53, 95% CI: 3.54-39.49) and other nonspecific respiratory symptoms compared with children with B. pertussis. Children with M. pneumoniae had very similar clinical presentations to those with a negative PCR, but were more likely to have radiologically confirmed pneumonia (adjusted OR: 5.48, 95% CI: 2.96-9.99) and were less likely to be diagnosed with a concomitant viral infection (adjusted OR: 0.32, 95% CI: 0.07-0.99). CONCLUSIONS: In children with suspected pertussis, the detection of M. pneumoniae is clinically relevant. However, the impact of this finding on patients' outcome is still unclear.

Impact of influenza vaccination on healthcare utilization - A systematic review.

INTRODUCTION: Although a vaccine-preventable disease, influenza causes approximately 3-5 million cases of severe illness and about 290,000-650,000 deaths worldwide, which occur primarily among people 65 years and older. Nonetheless, prevention of influenza and its complications rely mainly on vaccination. We aimed to systematically evaluate influenza vaccine effectiveness at reducing healthcare utilization in older adults, defined as the reduction of outpatient visits, ILI and influenza hospitalizations, utilization of antibiotics and cardiovascular events by vaccination status during the influenza season. METHODS: We searched MEDLINE, EMBASE, CINAHL, Cochrane Library and considered any seasonal influenza vaccine, excluding the pandemic (2009-10 season) vaccine. Reviewers independently assessed data extraction and quality assessment. RESULTS: Of the 8308 citations retrieved, 22 studies were included in the systematic review. Overall, two studies (9%) were deemed at moderate risk of bias, thirteen (59%) at serious risk of bias and seven (32%) at critical risk of bias. For outpatient visits, we found modest evidence of protection by the influenza vaccine. For all-cause hospitalization outcomes, we found a wide range of results, mostly deemed at serious risk of bias. The included studies suggested that the vaccine may protect older adults against influenza hospitalizations and cardiovascular events. No article meeting our inclusion criteria explored the use of antibiotics and ILI hospitalizations. The high heterogeneity between studies hindered the aggregation of data into a meta-analysis. CONCLUSION: The variability between studies prevented us from drawing a clear conclusion on the effectiveness of the influenza vaccine on healthcare utilization in older adults. Overall, the data suggests that the vaccine may result in a reduction of healthcare utilization in the older population. Further studies of higher quality are necessary.