RSV neutralization assays – Use in immune response assessment

Respiratory syncytial virus (RSV) is a leading cause of respiratory illness among children and infants worldwide, yet no licensed vaccine exists to reduce the risk of disease. At least 16 RSV vaccine candidates are currently in clinical development and many are designed to induce robust virus neutralizing immune responses. RSV neutralizing antibody (nAb)-mediated interventions such as intravenous immunoglobulin (IVIG) and palivizumab provide passive protection against serious lower respiratory tract disease due to RSV, validating nAbs as a correlate of protection. To identify correlates of protection for vaccine candidates that have demonstrated their protective efficacy, an investigator can use assays designed to measure nAb responses. However, there is no standard method of measurement; individual laboratories have developed their own methods to measure the ability of nAbs to reduce the infectivity of a defined virus dose in a variety of cell lines, leading to establishment of the broad variety of RSV neutralization assay formats currently in use.Standardizing the RSV neutralization assay is an essential step toward better assessment of nAb responses to vaccine candidates. Use of a common reference standard by all makes comparing the immunogenicity of different vaccine candidates feasible. In the context of vaccine development, the WHO 1^st International Standard for Antiserum to RSV (RSV IS) has been shown to be suitable for harmonizing results across laboratories and assay formats used to measure nAb titers to RSV/A and RSV/B in human sera.This review describes the broad variety of RSV virus neutralization assay formats currently in use and the importance of the RSV IS for harmonization of results across formats and across laboratories. It also outlines good practices for key assay components and data analysis to promote the quality and consistency of measuring RSV nAb titers in serum specimens.     

Tolerance of BNT162b2 mRNA COVI-19 vaccine in patients with a medical history of COVID-19 disease: A case control study

IntroductionStudies evaluating BNT162b2 mRNA Covid-19 vaccine safety excluded subjects with a previous history of COVID-19 infection. The aim of our study was to focus on the tolerance of this vaccine this population.MethodsAn anonymous self-reporting survey related to safety and tolerance of vaccine was completed by subjects 21 to 28 days after the first vaccine dose in two vaccination centers.ResultsSubjects with prior COVID-19 disease history (n = 61) had higher systemic reactions than subjects without any previous history (n = 1987) (45.9% vs 29.7%, p = 0.01). Asthenia, headache and fever were significantly more frequent in COVID-19 + group than negative group (25.6% vs 15.2% p = 0.045, 19.7% vs 9.3% p = 0.01, 6.5% vs 0.9% p = 0.003 respectively). Grade of severity was higher in COVID-19 + than in COVID-19 - group (p = 0.03).ConclusionOur study confirms a higher risk of side effects in patients with preexisting SARS-CoV-2 disease but with a good overall tolerance.     

Determinants of information diffusion in online communication on vaccination: The benefits of visual displays

ObjectiveSocial media are an increasingly important source of information on the benefits and risks of vaccinations, but the high prevalence of misinformation provides challenges for informed vaccination decisions. It is therefore important to understand which messages are likely to diffuse online and why, and how relevant aspects—such as scientific facts on vaccination effectiveness—can be made more comprehensible and more likely to be shared. In two studies, we (i) explore which characteristics of messages on flu vaccination facilitate their diffusion in online communication, and (ii) whether visual displays (i.e., icon arrays) facilitate the comprehension and diffusion of scientific effectiveness information.MethodsIn Study 1, 208 participants each rated a random sample of 15 out of 63 messages on comprehensibility, trustworthiness, persuasiveness, familiarity, informativeness, valence, and arousal, and then reported which information they would share with subsequent study participants. In Study 2 (N = 758), we employed the same rating procedure for a selected set of 9 messages and experimentally manipulated how scientific effectiveness information was displayed.ResultsStudy 1 illustrated that scientific effectiveness information was difficult to understand and thus did not diffuse well. Study 2 demonstrated that visual displays improved the understanding of this information, which could, in turn, increase its social impact.ConclusionsThe comprehensibility of scientific information is an important prerequisite for its diffusion. Visual displays can facilitate informed vaccination decisions by rendering important information on vaccination effectiveness more transparent and increasing the willingness to share this information.     

Serological response with Heplisav-B® in prior Hepatitis B vaccine non-responders living with HIV

BackgroundAs people living with HIV (PLWH) are at risk for contracting Hepatitis B Virus (HBV), they should be screened for HBV and vaccinated if not immune. Seroconversion rates in PLWH receiving traditional recombinant HBV vaccines (Engerix-B® and Recombivax-HB®) have historically been low with at most 70% achieving immunity. In 2017, a recombinant, adjuvanted HBV vaccine (Heplisav-B®) was approved for use in HIV-negative patients.Heplisav-B® has shown superior seroprotection in this population compared to Engerix-B® and Recombivax-HB®, as well as interim analysis showing higher seropositivity rates in patients undergoing dialysis. However, its efficacy in PLWH is currently unknown. This study evaluates the rate of seroconversion following Heplisav-B® administration in PLWH with previous HBV vaccination failure.MethodsRetrospective, cross-sectional study at The Brooklyn Hospital Center’s HIV primary care clinic in Brooklyn, NY. HIV-positive adults who received at least two doses of Heplisav-B® and had previously failed to seroconvert after vaccination with Engerix-B® or Recombivax-HB® were included. The primary outcome is the percentage of PLWH who became seropositive following Heplisav-B®.ResultsA total of 67 patients met the inclusion criteria. Twenty-five (37.3%) PLWH had failed at least 2 courses of recombinant vaccines. Fifty-eight (86.6%) PLWH became seropositive (Anti-HBs > 10 mIU/mL) at least two months after completing Heplisav-B®. For the 9 (13.4%) patients that did not develop immunity, 3 (33%) had a detectable HIV RNA and 3 (33%) had a CD4 count < 200 cells/uL³.ConclusionsHeplisav-B® was highly effective in achieving immunity to HBV in PLWH who failed non-adjuvanted recombinant vaccines.     

COVID-19 vaccine – Long term immune decline and breakthrough infections

BackgroundSince the introduction of BNT162b2 mRNA COVID-19 vaccine by Pfizer in late 2020, efficacy and immunogenicity waning of COVID-19 vaccines was reported, and decision making regarding a booster remains a top priority worldwide, a decision that should be made based on breakthrough infection rate and antibody titer decline overtime.MethodsWe conducted a 5-month longitudinal prospective study involving vaccinated healthcare personnel, who were tested monthly for antibody titer, and sampled biweekly and on clinical indication for SARS-COV-2 polymerase chain reaction (PCR), to determine antibody decline and breakthrough infection.Results100 participants were recruited to the study. Antibody titer reached the climate after one month of the second dose of the vaccine, and declined rapidly thereafter: the median antibody levels were 895; 22,266; 9,682; 2,554 and 1,401 AU/ml in the day of the second dose, and in one month interval thereafter, respectively. In other words, four months after vaccination, the mean antibody level was 6% of the peak levels. During the study period, 4 breakthrough infections were diagnosed, 2 of which were asymptomatic, and the remaining two were mild cases; sharp elevation of antibody titer was seen after infection.ConclusionAntibody titer drops rapidly one month after the second dose of the vaccine. All infections within the study period were mild or asymptomatic, after which titer elevations were seen.     

Evaluation of a Campylobacter jejuni N-glycan-ExoA glycoconjugate vaccine to reduce C. jejuni colonisation in chickens

Campylobacter jejuni is the leading bacterial cause of human gastroenteritis worldwide and handling or consumption of contaminated poultry meat is the key source of infection. Glycoconjugate vaccines containing the C. jejuni N-glycan have been reported to be partially protective in chickens. However, our previous studies with subunit vaccines comprising the C. jejuni FlpA or SodB proteins with up to two or three C. jejuni N-glycans, respectively, failed to elicit significant protection. In this study, protein glycan coupling technology was used to add up to ten C. jejuni N-glycans onto a detoxified form of Pseudomonas aeruginosa exotoxin A (ExoA). The glycoprotein, G-ExoA, was evaluated for efficacy against intestinal colonisation of White Leghorn chickens by C. jejuni strains M1 and 11168H relative to unglycosylated ExoA. Chickens were challenged with the minimum dose required for reliable colonisation, which was 10² colony-forming units (CFU) for strain M1 and and 10⁴ CFU for strain 11168H. Vaccine-specific serum IgY was detected in chickens vaccinated with both ExoA and G-ExoA. However, no reduction in caecal colonisation by C. jejuni was observed. While the glycan dose achieved with G-ExoA was higher than FlpA- or SodB-based glycoconjugates that were previously evaluated, it was lower than that of glycoconjugates where protection against C. jejuni has been reported, indicating that protection may be highly sensitive to the amount of glycan presented and/or study-specific variables.     

Priming with social benefit information of vaccination to increase acceptance of COVID-19 vaccines

Vaccine hesitancy can be heightened due to increasing negative reports about vaccines. Emphasizing the social benefits of vaccination may shift individual attention from individual to social benefit of vaccination and hence promote prosocial vaccination. In six rounds of a population-based survey conducted over one major community epidemic of coronavirus disease 2019 (COVID-19) in Hong Kong from June to November 2020, we manipulated the question asking about acceptance of a COVID-19 vaccine with or without emphasizing the social benefit of vaccination against COVID-19 (prosocial priming) and monitored the changes of vaccine confidence by news media sentiment on vaccines. Population-weighted percentages of accepting COVID-19 vaccines by priming condition and vaccine confidence were compared across survey rounds. Logit regression models assessed the main effect of prosocial priming and the modification effects of vaccine confidence and perceived personal risk from COVID-19 on acceptance of COVID-19 vaccines. We found that prosocial priming significantly increased acceptance of COVID-19 vaccines across all survey rounds except for Round 3 when incidence of COVID-19 reached a peak. Vaccine confidence significantly declined in Round 6 when news media sentiment on vaccines became predominantly negative. The effect of prosocial priming on promoting vaccine acceptance was significantly greater in participants with low vaccine confidence and those perceiving the severity of COVID-19 to be mild/very mild. Our study suggests that packaging vaccination against COVID-19 as a prosocial behaviour can help overcome low vaccine confidence and promote prosocial vaccination particularly when disease incidence temporarily declines and the public perceive low severity of COVID-19.     

The cost-effectiveness of starting 23-valent pneumococcal polysaccharide vaccine and influenza vaccination at 50 vs. 65 years: A comparative modelling study

ObjectivesPneumococcal infection is a leading cause of morbidity and mortality. We aimed to evaluate the cost-effectiveness of 23-valent polysaccharide vaccine (PPV23) together with influenza vaccination or pneumococcal vaccination alone in adults starting from 50 years vs. 65 years in Hong Kong.MethodsA hypothetical population of 100,000 older adults was included in a Markov model with age ranging from 50 to 85 years to calculate the cost and quality-adjusted life-years (QALYs) gained for vaccination strategies, including: (1) annual influenza vaccine and PPV23 at 50 and 65 years; (2) annual influenza vaccine and PPV23 at 65 years (similar with the current vaccination programme); (3) PPV23 at 50 and 65 years; (4) PPV23 at 65 years; and (5) no vaccination. We evaluated the incremental cost-effectiveness ratio (ICER) and used Monte Carlo simulation for probabilistic sensitivity analysis. The cost-effectiveness threshold was extracted from previous literature.ResultsIn comparison with no vaccination, all strategies were cost-effective with ICERs less than the threshold (US$24,302 per QALY gained). When compared with no vaccination, strategies 1–4 saved US$ 49.5, US$ 94.9, US$ 584.3, and US$ 1114.2 to gain one QALY respectively. In comparison with strategy 2, strategy 1 spent US$ 195.3 to gain one QALY, whilst strategies 3 and 4 showed less effectiveness with increased costs.ConclusionsAll vaccination strategies were cost-effective, among which the strategy of PPV23 at 50/65 years with annual influenza vaccine was cost-effective even in comparison with current vaccination programme. These findings could help inform the design and implementation of vaccination strategies.     

Aggregating human judgment probabilistic predictions of the safety,efficacy, and timing of a COVID-19 vaccine

Safe, efficacious vaccines were developed to reduce the transmission of SARS-CoV-2 during the COVID-19 pandemic. But in the middle of 2020, vaccine effectiveness, safety, and the timeline for when a vaccine would be approved and distributed to the public was uncertain. To support public health decision making, we solicited trained forecasters and experts in vaccinology and infectious disease to provide monthly probabilistic predictions from July to September of 2020 of the efficacy, safety, timing, and delivery of a COVID-19 vaccine. We found, that despite sparse historical data, a linear pool—a combination of human judgment probabilistic predictions—can quantify the uncertainty in clinical significance and timing of a potential vaccine. The linear pool underestimated how fast a therapy would show a survival benefit and the high efficacy of approved COVID-19 vaccines. However, the linear pool did make an accurate prediction for when a vaccine would be approved by the FDA. Compared to individual forecasters, the linear pool was consistently above the median of the most accurate forecasts. A linear pool is a fast and versatile method to build probabilistic predictions of a developing vaccine that is robust to poor individual predictions. Though experts and trained forecasters did underestimate the speed of development and the high efficacy of a SARS-CoV-2 vaccine, linear pool predictions can improve situational awareness for public health officials and for the public make clearer the risks, rewards, and timing of a vaccine.     

A phase 1/2 randomised placebo-controlled study of the COVID-19 vaccine mRNA-1273 in healthy Japanese adults: An interim report

IntroductionThe mRNA vaccine, mRNA-1273/TAK-919, encodes the prefusion-stabilised spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report interim results of the first study evaluating safety and immunogenicity of mRNA-1273 in healthy Japanese participants.MethodsThis phase 1/2, randomised, observer-blind, placebo-controlled trial, conducted in Japan (two sites), enrolled healthy adults aged ≥ 20 years with no prior exposure to investigational coronavirus vaccines/treatments, and no known history/risk of SARS-CoV-2 infection. Participants were stratified by age (< 65/≥ 65 years) and randomised to receive two doses of 100 μg mRNA-1273 or placebo administered as intramuscular injections 28 days apart. Primary outcomes were safety and immunogenicity assessed by anti-SARS-CoV-2-spike protein-binding antibody level (bAb). A secondary outcome was SARS-CoV-2 neutralising antibody (nAb) response.ResultsParticipants were enrolled between 21 January and 3 February 2021, and 200 were randomised: mRNA-1273, n = 150 (< 65 years, n = 100; ≥ 65 years, n = 50); placebo, n = 50 (< 65 years, n = 40; ≥ 65 years, n = 10). Solicited adverse events (AEs) through 7 days after each vaccination occurred in 144/150 (96%) and 19/50 (38%) participants in the mRNA-1273 and placebo arms, respectively. In the mRNA-1273 arm, injection-site pain, myalgia and fatigue were the most frequently reported solicited AEs after each vaccination, irrespective of age. Robust immune responses occurred with mRNA-1273 (n = 147) with a bAb geometric mean fold rise (95% confidence interval [CI]) from baseline of 1009 (865, 1177) and a nAb of 21.7 (19.8, 23.8) at day 57. Seroconversion rates (95% CI) for bAb and nAb were both 100% (97.5, 100) at day 57. No such response occurred with placebo (n = 49).ConclusionTwo doses of 100 μg mRNA-1273 given 28 days apart demonstrated an acceptable safety profile and induced significant anti-SARS-CoV-2 immune responses in a Japanese population aged ≥ 20 years. Funding: Takeda Pharmaceutical Company Limited and Japan Agency for Medical Research and Development (AMED). ClinicalTrials.gov: NCT04677660.