High Vaccine Efficacy Research Articles

Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City.

The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February-April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. The median age of patients in the study was 48 years; 7 required hospitalization and 1 died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in χ2 and McNemar tests (P > 0.1), highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.

Reliance on Vaccine-Only Pandemic Mitigation Strategies is Compromised by Highly Transmissible COVID-19 Variants: A Mathematical Modelling Study

Background: New SARS-CoV-2 variants, such as B1.617.2 (Delta), are appearing that have higher transmissibility than the original Wuhan strain. Throughout 2020, the only responses available to mitigate SARS-CoV-2 transmission were non-pharmaceutical interventions such as social distancing, community lockdowns and quarantine measures. COVID-19 vaccines are now available and being administered, yet in countries with high vaccination rates, such as the United Kingdom and United States, a resurgence in COVID-19 cases has been observed and the Delta variant implicated. Of concern is the possibly lower efficacy of the ChAdOx1-S (AstraZeneca) vaccine against the Delta variant. We analysed alternative vaccination strategies to determine those most likely to mitigate future COVID-19 Delta outbreaks.Methods: We applied detailed agent-based community models to evaluate the impact of SARS-Cov-2 vaccination under a range of coverage levels, vaccine efficacies, and ages of those vaccinated. This was conducted with and without community lockdowns activated in response to significant outbreaks of highly transmissible SARS-CoV-2 variants. Critically, we determined whether vaccination in adolescents is required. We evaluated two vaccine types with different effectiveness potential against transmission.Findings: High vaccine efficacy and extremely high vaccination coverage of 90% of adults and adolescents was shown to be required to mitigate highly transmissible variants such as Delta without activation of strong lockdown measures, in contrast to the Alpha variant. We further demonstrated that inclusion of adolescent vaccination and use of mRNA vaccines (BNT162b2 Pfizer) to boost immunity levels among those previously vaccinated with the ChAdOx1-S (AstraZeneca) vaccine was effective in significantly reducing the scale of future COVID-19 outbreaks. Results suggest that greater than 70% vaccine coverage in those 12 years and older, together with a vaccine boosting regimen, would be sufficient to halt a rapidly growing Delta outbreak if coupled with early activation of moderate lockdown measures, which permit schools to remain open.Interpretation: Increasing the number of immune persons in the community by including adolescents in a vaccination program, and by applying “third dose” boosting vaccinations, may prevent B1.617.2 Delta outbreaks from rapidly growing without the need for strict lockdown measures. Under achievable 80% vaccination coverage moderate social distancing measures may be sufficient to prevent future large scale outbreaks. Compared to strict lockdown, such limited social distancing measures would substantially increase workplace numbers and allow schools to remain open, with attendant economic, mental and physical wellbeing, and educational benefits.Funding: The Department of Health, Western Australia (Future Health Research andInnovation Fund) and the Department of Health, Queensland, Australia.Declaration of Interest: GM reports research funding from the Department of Health, Queensland outside the submitted work. JC and DW declare no competing interests.

Benefit of COVID-19 vaccination accounting for potential risk compensation

People receiving COVID-19 vaccines may subsequently markedly increase their previously suppressed exposure risk. A simple model can evaluate the benefit of vaccination to the vaccinated (index) person and others exposed to that person; and calculate the amount of risk compensation required to eliminate all the benefits or to halve the benefit. As shown, 2.5-fold increase in exposure will eliminate the benefit of a vaccine of moderate efficacy (E = 0.6) unless the probability of infection in the population of interest is very high. With very high vaccine efficacy (E = 0.95), substantial benefit is maintained except in situations where there is a very low probability of infection in the population. If the vaccine efficacy decreases to 0.8, the benefit gets eroded easily with modest risk compensation. Risk compensation may markedly affect the benefit of COVID-19 vaccination, especially if vaccine efficacy in real-life or specific high-risk populations (e.g., nursing home residents) is not very high.

Humoral immune responses during SARS-CoV-2 mRNA vaccine administration in seropositive and seronegative individuals

BackgroundThe global pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with the SARS-CoV-2 virus. Currently, there are three approved vaccines against SARS-CoV-2 in the USA, including two based on messenger RNA (mRNA) technology that has demonstrated high vaccine efficacy. We sought to characterize humoral immune responses, at high resolution, during immunization with the BNT162b2 (Pfizer-BioNTech) vaccine in individuals with or without prior history of natural SARS-CoV-2 infection.MethodsWe determined antibody responses after each dose of the BNT162b2 SARS-CoV-2 vaccine in individuals who had no prior history of SARS-CoV-2 infection (seronegative) and individuals that had previous viral infection 30–60 days prior to first vaccination (seropositive). To do this, we used both an antibody isotype-specific multiplexed bead-based binding assays targeting multiple SARS-CoV-2 viral protein antigens and an assay that identified potential SARS-CoV-2 neutralizing antibody levels. Moreover, we mapped antibody epitope specificity after immunization using SARS-CoV-2 spike protein peptide arrays.ResultsAntibody levels were significantly higher after a single dose in seropositive individuals compared to seronegative individuals and were comparable to levels observed in seronegative individuals after two doses. While IgG was boosted by vaccination for both seronegative and seropositive individuals, only seronegative individuals had increased IgA or IgM antibody titers after primary immunization. We identified immunodominant peptides targeted on both SARS-CoV-2 spike S1 and S2 subunits after vaccination.ConclusionThese findings demonstrated the antibody responses to SARS-CoV-2 immunization in seropositive and seronegative individuals and provide support for the concept of using prior infection history as a guide for the consideration of future vaccination regimens. Moreover, we identified key epitopes on the SARS-CoV-2 spike protein that are targeted by antibodies after vaccination that could guide future vaccine and immune correlate development.

Evaluating Vaccine Efficacy Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Although interim results from several large, placebo-controlled, phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic coronavirus disease 2019 (COVID-19), it is unknown how effective the vaccines are in preventing people from becoming asymptomatically infected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between 2 antibody or reverse-transcription polymerase chain reaction (RT-PCR) tests. Additional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment of participants or crossover of placebo recipients to the vaccine arm before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, staggered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies that mimic the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates.

Efficacy information influences intention to take COVID-19 vaccine.

ObjectivesA successful response to the COVID‐19 pandemic requires achieving high levels of vaccine uptake. We tested whether directly contrasting the high efficacy of COVID‐19 vaccines with the lower efficacy of the annual flu vaccine would increase intentions to take a COVID‐19 vaccine.DesignA pre‐registered online study of 481 participants compared four information conditions: (1) no information; (2) COVID‐19 Vaccine Information Only; and COVID‐19 Vaccine Information combined with flu vaccine information suggesting either (3) 60% efficacy or (4) 40% efficacy; we measured COVID‐19 and flu vaccine intentions along with several other vaccine‐related variables.MethodsThe Prolific platform was used to recruit 481 UK participants (64% female; aged between 18 and 85 years) who had been pre‐screened to have intermediate levels of vaccine hesitancy. After reading a short text (~200 words) about COVID‐19 vaccines, participants were asked about their vaccination intentions.ResultsProviding information about the safety and efficacy of the new COVID‐19 vaccines resulted in vaccination intentions that were, on average, 0.39 standard deviations (SDs) higher than those in the no information condition; providing the same COVID vaccine efficacy information in the context of information about flu vaccine efficacy resulted in a further significant increase in vaccination intentions that were 0.68 SD higher than those in the no information condition. This positive contrast effect for the COVID‐19 vaccine was not associated with reduced flu vaccine intentions.ConclusionsVaccination intentions can be strengthened through a simple messaging intervention that utilizes context effects to increase perceived response efficacy.

Interpreting vaccine efficacy trial results for infection and transmission

Randomized controlled trials (RCTs) have shown high efficacy of multiple vaccines against SARS-CoV-2 disease (COVID-19), and recent studies have shown the vaccines are also effective against infection. Evidence for the effect of each of these vaccines on ability to transmit the virus is also beginning to emerge. We describe an approach to estimate these vaccines’ effects on viral positivity, a prevalence measure which under the reasonable assumption that vaccinated individuals who become infected are no more infectious than unvaccinated individuals forms a lower bound on efficacy against transmission. Specifically, we recommend separate analysis of positive tests triggered by symptoms (usually the primary RCT outcome) and cross-sectional prevalence of positive tests obtained regardless of symptoms. The odds ratio of carriage for vaccine vs. placebo provides an unbiased estimate of vaccine effectiveness against viral positivity, under certain assumptions, and we show through simulations that likely departures from these assumptions will only modestly bias this estimate. Applying this approach to published data from the RCT of the Moderna vaccine, we estimate that one dose of vaccine reduces the potential for transmission by at least 61%, possibly considerably more. We describe how these approaches can be translated into observational studies of vaccine effectiveness.

Kidney Transplant Recipient Attitudes Toward a SARS-CoV-2 Vaccine.

Background.A widely accepted severe acute respiratory syndrome 2 (SARS-CoV-2) vaccine could protect vulnerable populations, but the willingness of solid organ transplant recipients (SOTRs) to accept a potential vaccine remains unknown.Methods.We conducted a national survey of 1308 SOTRs and 1617 non-SOTRs between November 11 and December 2, 2020 through the network of the National Kidney Foundation.Results.Respondents were largely White (73.2%), female (61.1%), and college graduates (56.2%). Among SOTRs, half (49.5%) were unsure or would be unwilling to receive a SARS-CoV-2 vaccine once available. Major concerns included potential side effects (85.2%), lack of rigor in the testing and development process (69.7%), and fear of incompatibility with organ transplants (75.4%). Even after the announcement of the high efficacy of the mRNA-1273 vaccine (Moderna Inc.) at the time of survey distribution, likeliness to receive a vaccine only slightly increased (53.5% before announcement versus 57.8% after the announcement). However, 86.8% of SOTRs would accept a vaccine if recommended by a transplant provider.Conclusions.SOTRs reported skepticism in receiving a potential SARS-CoV-2 vaccine, even after announcements of high vaccine efficacy. Reassuringly, transplant providers may be the defining influence in vaccine acceptance and will likely have a critical role to play in promoting vaccine adherence.

Pandemic moves and countermoves: vaccines and viral variants

In the past few months, the results of several phase 3 studies showing high vaccine efficacy against SARS-CoV-2 and the subsequent rapid regulatory approval and roll-out of several vaccines have ignited much optimism. However, this optimism has been dampened by the emergence of several new virus variants that are more transmissible and less sensitive to vaccine-induced antibodies.1–6 The extent to which emerging variants affect the efficacy of vaccines appears to vary considerably between vaccines and variants.

Evaluating the Long-term Efficacy of Coronavirus Disease 2019 (COVID-19) Vaccines.

Large-scale deployment of safe and durably effective vaccines can curtail the coronavirus disease-2019 (COVID-19) pandemic. However, the high vaccine efficacy (VE) reported by ongoing phase 3 placebo-controlled clinical trials is based on a median follow-up time of only about 2 months, and thus does not pertain to long-term efficacy. To evaluate the duration of protection while allowing trial participants timely access to efficacious vaccine, investigators can sequentially cross participants over from the placebo arm to the vaccine arm. Here, we show how to estimate potentially time-varying placebo-controlled VE in this type of staggered vaccination of participants. In addition, we compare the performance of blinded and unblinded crossover designs in estimating long-term VE.

Risk of SARS-CoV-2 reinfection after natural infection

Risk of SARS-CoV-2 reinfection after natural infection

Principal surrogates in context of high vaccine efficacy

Abstract Objectives The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro, A., and F. Tibaldi. 2019. “Assessing Correlates of Protection in Vaccine Trials: Statistical Solutions in the Context of High Vaccine Efficacy.” BMC Medical Research Methodology 19: 47 showed that the rare infections observed in the vaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and meta-analysis. The objective of this work is to investigate the impact of this problem on another statistical method for the assessment of CoPs called Principal stratification. Methods We perform simulation experiments to investigate the effect of high vaccine efficacy on the performance of the Principal Stratification approach. Results Similarly to the Prentice framework, simulation results show that the power of the Principal Stratification approach decreases when the VE grows. Conclusions It can be challenging to validate principal surrogates (and statistical surrogates) for vaccines with very high vaccine efficacy.

Benefit of COVID-19 Vaccination Accounting for Potential Risk Compensation

Newly developed vaccines have tremendous potential in the fight against the COVID-19 pandemic. Risk compensation is the phenomenon where people receiving vaccines or other preventive measures may subsequently increase their previously suppressed exposure risk. Here a parsimonious mathematical model is presented that aims to evaluate the benefit of vaccination to the vaccinated (index) person and others exposed to that person; and calculate the amount of risk compensation required to eliminate all the benefit or to halve the benefit. As shown, 2.5-fold increase in exposure may eliminate the benefit of a vaccine of moderate efficacy (E=0.6) unless the probability of infection in the population of interest is very high. With very high vaccine efficacy (E=0.95), substantial benefit is maintained except in situations where there is very low probability of infection in the population. If the vaccine efficacy decreases to 0.8, the benefit may get eroded easily with modest risk compensation. Risk compensation may markedly affect the benefit of COVID-19 vaccination, especially if vaccine efficacy in real-life or specific high-risk populations (e.g. nursing home residents) is not very high.

Attitude to vaccinate against coronavirus disease 2019 of high school students in chonburi province, Thailand: A study of grade 10-12 students of princess chulabhorn science school

Background: COVID-19 or coronavirus disease 2019 has rapidly affected all aspects of life around and becomes a major threat to public health around the world. One of the most important actions that need to be taken to stop the pandemic is vaccinations. Managing the COVID-19 pandemic in the long term, unwillingness to receive vaccinations and negative attitudes toward vaccines are major barriers. Objectives: This study aimed to investigate community knowledge, risk perceptions, and attitudes toward COVID-19 vaccinations among high school students in Chonburi, Thailand. Materials and Methods: The study was conducted using a questionnaire. A total of 303 students participated. COVID-19-related knowledge, risk perception, and attitude toward COVID-19 vaccines were assessed. Independent t-test and ANOVA were used to analyze differences between outcomes and sociodemographic. Attitudes toward vaccination were analyzed by a generalized linear model. Results: Students revealed a moderate level of COVID-19-related knowledge, correctly answering 7.09 (SD = 1.56) questions in a total of 10, a moderate level of risk perception of getting COVID-19, average score was 9.7 (SD = 3.03) of 12, and attitude toward vaccine against, the average scores at 3.02 (SD = 1.64), questions in a total of 21. Conclusion: This study revealed a moderate level of knowledge about COVID-19, risk perception, and attitude against COVID-19 vaccination among high school students at Princess Chulabhorn Science School, Chonburi, Thailand. Moreover, it reinforces that there is no relation between those factors and the attitude for accepting COVID-19 vaccines. However, the reasons behind the attitude against the COVID-19 vaccination were efficacy of vaccines. News about the side effects of the vaccines, such as chest pain, muscle pain, dizziness, fatigue, breathing problems, numbness, and facial tics, was widespread among people and brought more attitudes against COVID-19 vaccination. Considering precisely, increasing efficacy of the vaccine will lead to higher vaccine acceptance. Therefore, to control the pandemic in the long term, providing high vaccine efficacy will be one of the recommended solutions.

7. Can Recombinant Zoster Vaccine Administration Decrease the Use of Herpes Zoster-related Pain Medication Across Randomized Controlled Studies?

BackgroundOlder and immunocompromised adults are at increased risk for herpes zoster (HZ) and often experience persistent, severe HZ-related pain, impacting their quality of life and activities of daily living. High vaccine efficacy (VE) of the adjuvanted recombinant zoster vaccine (RZV) in preventing HZ and reducing severe and clinically significant HZ-related pain has been shown in adults ≥ 50 years of age (YOA; ZOE-50 study; NCT01165177), ≥ 70 YOA (ZOE-70; NCT01165229) and ≥ 18 YOA undergoing autologous hematopoietic stem cell transplantation (ZOE-HSCT; NCT01610414).MethodsIn patients with confirmed HZ from the above phase III, randomized, placebo-controlled studies, we analyzed VE of RZV in reducing the duration of clinically significant HZ-related pain and in reducing the use and duration of HZ-related pain medication. Pain was assessed by the Zoster Brief Pain Inventory (ZBPI). Use of all HZ-related medication was recorded.ResultsVE in reducing the duration of clinically significant HZ-related pain (ZBPI pain score ≥3) during HZ episodes was 38.5% (p-value: 0.0099) in RZV-vaccinated patients from the ZOE-HSCT study compared to placebo. A similar trend (not statistically significant) was observed in the ZOE-50 (VE: 26.9%; p-value: 0.4318) and ZOE-70 (VE: 28.4%; p-value: 0.1877) studies. VE in reducing the use (Table 1) and duration (Table 2) of HZ-related pain medication was 39.6% (p-value: 0.0083) and 49.3%(p-value: 0.0404), respectively, in the ZOE-70 study; corresponding positive VE estimates were also seen in the ZOE-50 and ZOE-HSCT studies. Non-opioids were used by 61.2%, 44.3% and 22.1% of patients in the ZOE-50, ZOE-70 and ZOE-HSCT studies, respectively; weak opioids by 18.6%, 13.0% and 10.8% of patients, and strong opioids by 8.0%, 2.0% and 5.3% of patients (Table 3).Table 1. Reduction in the use of HZ-related pain medication in patients with confirmed HZ Table 2. Reduction in the duration of HZ-related pain medication use in patients with confirmed HZ Table 3. HZ-related medication types in patients with confirmed HZ ConclusionIn addition to a high VE in preventing HZ in these studies, we also observed an attenuation of HZ-related pain, and thus lower use and duration of pain medication in breakthrough cases after RZV vaccination, thereby potentially improving patient quality of life. Funding: GlaxoSmithKline Biologicals SA Acknowledgment: Kristel Vercauteren/Sander Hulsmans (Modis c/o GSK) provided medical writing/editorial supportDisclosures Joon Hyung Kim, MD, GSK (Employee, Shareholder) Robert Johnson, MD, FRCA, GSK (Other Financial or Material Support, I accept no fees but have had expense reimbursement in the past.) Martina Kovac, MD, GSK (Other Financial or Material Support, I was an employee of GSK at the time of the study) Anthony L. Cunningham, MBBS, MD, FRACP, FRCPA, GSK (Consultant) Srikanth Emmadi, MSc, GSK (Employee) Keith Sullivan, MD, FASTCT, GSK (Consultant) Alemnew F. Dagnew, MD, GSK group of companies (Employee, Shareholder) Desmond Curran, PhD, GSK (Employee, Shareholder) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration)

8. The Adjuvanted Recombinant Zoster Vaccine (RZV) Confers Long-term Protection Against Herpes Zoster: Interim Results of an Extension Study (ZOSTER-049) of Two Clinical Trials (ZOE-50 and ZOE-70)

BackgroundTwo large-scale phase 3 clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]) demonstrated that, in adults ≥ 50 years of age followed over a mean period of 3.1 and 3.7 years respectively, the adjuvanted recombinant zoster vaccine (RZV) was efficacious against herpes zoster (HZ), highly immunogenic and had a clinically acceptable safety profile. In this extension study (ZOSTER-049 [NCT02723773]), RZV-induced immunogenicity persistence and long-term vaccine efficacy (VE) against HZ were evaluated; we report interim results after at least 2 years of follow-up (starting and ending ≈5.1 and 7.1 years, respectively, after initial vaccination during the parent studies).MethodsThe study design is detailed in Figure 1. Primary objective: VE against HZ over the ZOSTER-049 study. Secondary objectives: VE against HZ from 1 month post-dose 2 in ZOE-50/-70 until the end of observation for year (Y)2 of ZOSTER-049, persistence of vaccine-induced humoral immunogenicity (HI) in terms of anti-gE antibody concentrations (by ELISA) and cell-mediated immune (CMI) response in terms of frequency of gE-specific CD4+ T-cells (by intracellular cytokine staining).Figure 1. Study design of the extension study in relation to the parent studies. ZOSTER-049 study procedures, timing, endpoints and cohorts ResultsOf the 7,413 participants enrolled in ZOSTER-049, 7,277 were included in the VE analysis (Figure 2) and 6,972 reached Y2 of this study. The overall VE against HZ during at least 2 years of follow-up in ZOSTER-049 was 84.0% (95% confidence interval [CI]: 75.9–89.8%). From 1 month post-dose 2 in the ZOE-50/-70 studies until the end of observation for Y2 of ZOSTER-049, the overall VE was 90.9% (95% CI: 88.2–93.2%). Anti-gE antibody concentrations persisted ≈6 times above pre-vaccination levels up to Y8 after vaccination (Figure 3A) and the frequency of gE-specific CD4[2+] T-cells remained above baseline from Y6 to Y8 after vaccination (i.e. until the end of observation for Y2 of ZOSTER-049) (Figure 3B).Figure 2. Demographic characteristics of participants included in the ZOSTER-049 study, for the analysis of vaccine efficacy against herpes zoster (mTVC) Figure 3. Long-term persistence of humoral immunogenicity (HI) and cell-mediated immune (CMI) responses up to year 8 post-vaccination dose 2 administered in the ZOE-50/-70 studies ConclusionRZV demonstrated high VE against HZ until the end of the observation period for this Y2 interim analysis. The HI and CMI responses remained stable and high until the end of observation (i.e. 7.1 years after initial vaccination). Funding: GlaxoSmithKline Biologicals SA Acknowledgements: LA Truta/S Hulsmans (Modis c/o GSK) provided writing/editorial supportDisclosures Céline Boutry, PhD, Aixial (Consultant) Andrew Hastie, MD, GSK group of companies (Employee) Meng Shi, MS, GSK group of companies (Employee) Javier Diez-Domingo, MD, GSK group of companies (Board Member, Scientific Research Study Investigator, Advisor or Review Panel member)MSD (Board Member, Scientific Research Study Investigator, Advisor or Review Panel member) Paola Pirrotta, PharmD, GSK group of companies (Employee) George Kalema, PhD, GSK group of companies/Keyrus Biopharma (Consultant) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration)

Accuracy, efficacy and safety of dengue CYD-TDV pre-vaccination screening with 5 existing IgG serotests: Retrospective analysis of phase III trials

Background: Post-hoc analyses of CYD-TDV vaccine efficacy trials indicated that dengue seropositive vaccinees experienced protection against dengue hospitalization and severe dengue, while seronegative vaccinees were at increased risk for these outcomes. Pre-vaccination screening has been recommended by WHO to identify those with prior dengue infection (PDI) who would benefit from vaccination. We retrospectively assessed the concept of pre-vaccination screening by estimating vaccine efficacy (VE) in test-positive individuals using five marketed serotests. Methods and materials: Pre-vaccination sera obtained from subjects in the immunogenicity subsets of CYD14 and CYD15 (n ≥ 3841) were tested by two ELISAs and three rapid diagnostic tests (RDT). Reference serostatus was determined using measured dengue PRNT90, PRNT50 and NS1 IgG ELISA pre-vaccination, enabling estimation of serotest performance. VE against symptomatic virologically-confirmed dengue (VCD) over 25 months and dengue hospitalization over 6 years from first injection was assessed in test+ subjects using a Cox regression model. Pooled VE [(1 − Hazard Ratio) × 100] across all ages (2–16 years) is presented. Results: Assay specificity was high for all tests: Euroimmun-IgG-ELISA, 98.8% (95% CI: 97.9–99.3); Panbio-Indirect-IgG-ELISA, 99.2% (98.5–99.6); Biocan-RDT, 99.0%(98.3–9.5); SDBioline-RDT, 96.0% (94.8–97.1); and CTK-RDT, 99.5% (98.9–99.8). Sensitivity of the Euroimmun-ELISA (89.2%[87.9–90.3]) and Panbio-ELISA (92.5% [91.4–93.5]) were substantially higher than that of the SDBioline-RDT (71.1% [69.3–72.8]), Biocan-RDT (52.5% [50.6–54.4]) and CTK-RDT (47.6% [45.7–49.5]). For each serotest, vaccination of test+ subjects was associated with high VE against VCD (Table 1). Significant protection against hospitalized VCD was evident for test+ subjects with each serotest except CTK-RDT, for which the estimate was favorable, but the lower 95% CI crossed the null.Table 1VE against VCD and dengue hospitalization in test+ subjects.EndpointImmunoassayaIgG readout only.IncidencebCases/100 person-years. (95% CI)VE (95% CI)CYD-TDVPlaceboVCD (25 months)ELISA-Euroimmun0.4 (0.2–0.6)3.0 (2.2–4.0)88.3 (77.4–93.9)ELISA-Panbio0.4 (0.2–0.6)3.0 (2.2–3.9)87.6 (76.7–93.4)RDT-Biocan0.2 (0.1–0.6)2.0 (1.2–3.0)88.8 (66.9–96.2)RDT-SDBioline0.5 (0.2–0.8)2.7 (1.9–3.8)82.8 (66.9–91.1)RDT-CTK0.2 (0.0–0.5)1.7 (1.0–2.8)89.7 (64.6–97.0)Hospitalized VCD (6 years)ELISA-Euroimmun0.1 (0.0–0.2)0.4 (0.2–0.6)72.8 (38.9–87.9)ELISA-Panbio0.1 (0.1–0.2)0.5 (0.3–0.7)77.5 (52.8–89.3)RDT-Biocan<0.1 (0.0–0.1)0.3 (0.1–0.5)92.4 (37.8–99.1)RDT-SDBioline<0.1 (0.0–0.1)0.3 (0.2–0.6)87.2 (54.5–96.4)RDT-CTK<0.1 (0.0–0.2)0.2 (0.1–0.5)73.7 (−5.1 to 93.4)a IgG readout only.b Cases/100 person-years. Open table in a new tab Conclusion: Using five dengue IgG immunoassays, vaccination of test+ subjects is evidently safe and efficacious. The more sensitive ELISAs offer the distinct advantage of identifying a larger proportion of individuals who would benefit from vaccination.

Constructing conjugate vaccine against Salmonella Typhimurium using lipid-A free lipopolysaccharide

BackgroundSalmonella enterica serotype Typhimurium is a nontyphoidal and common foodborne pathogen that causes serious threat to humans. There is no licensed vaccine to prevent the nontyphoid bacterial infection caused by S. Typhimurium.MethodsTo develop conjugate vaccines, the bacterial lipid-A free lipopolysaccharide (LFPS) is prepared as the immunogen and used to synthesize the LFPS–linker–protein conjugates 6a–9b. The designed bifunctional linkers 1–5 comprising either an o-phenylenediamine or amine moiety are specifically attached to the exposed 3-deoxy-D-manno-octulosonic acid (Kdo), an α-ketoacid saccharide of LFPS, via condensation reaction or decarboxylative amidation. In addition to bovine serum albumin and ovalbumin, the S. Typhimurium flagellin (FliC) is also used as a self-adjuvanting protein carrier.ResultsThe synthesized conjugate vaccines are characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and fast performance liquid chromatography (FPLC), and their contents of polysaccharides and protein are determined by phenol–sulfuric acid assay and bicinchoninic acid assay, respectively. Enzyme-linked immunosorbent assay (ELISA) shows that immunization of mouse with the LFPS–linker–protein vaccines at a dosage of 2.5 μg is sufficient to elicit serum immunoglobulin G (IgG) specific to S. Typhimurium lipopolysaccharide (LPS). The straight-chain amide linkers in conjugates 7a–9b do not interfere with the desired immune response. Vaccines 7a and 7b derived from either unfractionated LFPS or the high-mass portion show equal efficacy in induction of IgG antibodies. The challenge experiments are performed by oral gavage of S. Typhimurium pathogen, and vaccine 7c having FliC as the self-adjuvanting protein carrier exhibits a high vaccine efficacy of 74% with 80% mice survival rate at day 28 post the pathogen challenge.ConclusionsThis study demonstrates that lipid-A free lipopolysaccharide prepared from Gram-negative bacteria is an appropriate immunogen, in which the exposed Kdo is connected to bifunctional linkers to form conjugate vaccines. The decarboxylative amidation of Kdo is a novel and useful method to construct a relatively robust and low immunogenic straight-chain amide linkage. The vaccine efficacy is enhanced by using bacterial flagellin as the self-adjuvanting carrier protein.Graphical abstract

Vaccines against Coronaviruses: The State of the Art.

The emerging epidemic caused by the new coronavirus SARS-CoV-2 represents the most important socio-health threat of the 21st century. The high contagiousness of the virus, the strong impact on the health system of the various countries and the absence to date of treatments able to improve the prognosis of the disease make the introduction of a vaccine indispensable, even though there are currently no approved human coronavirus vaccines. The aim of the study is to carry out a review of the medical literature concerning vaccine candidates for the main coronaviruses responsible for human epidemics, including recent advances in the development of a vaccine against COVID-19. This extensive review carried out on the vaccine candidates of the main epidemic coronaviruses of the past has shown that the studies in animal models suggest a high efficacy of potential vaccines in providing protection against viral challenges. Similar human studies have not yet been carried out, as the main trials are aimed at assessing mainly vaccine safety and immunogenicity. Whereas the severe acute respiratory syndrome (SARS-CoV) epidemic ended almost two decades ago and the Middle East respiratory syndrome (MERS-CoV) epidemic is now better controlled, as it is less contagious due to the high lethality of the virus, the current SARS-CoV-2 pandemic represents a problem that is certainly more compelling, which pushes us to accelerate the studies not only for the production of vaccines but also for innovative pharmacological treatments. SARS-CoV-2 vaccines might come too late to affect the first wave of this pandemic, but they might be useful if additional subsequent waves occur or in a post-pandemic perspective in which the virus continues to circulate as a seasonal virus.

Measles outbreak investigation in Ginnir district of Bale zone, Oromia region, Southeast Ethiopia, May 2019.

IntroductionMeasles is a vaccine-preventable viral infection of humans, primarily affecting children <5 years. During early 2019, outbreak of measles occurred in Ginnir district of Bale zone, Southeast Ethiopia. We investigated to describe the outbreak and identify risk factors.MethodsWe conducted a descriptive and 1:2 unmatched case-control study in Ginnir district from March 18 to April 29, 2019. Fifty-six cases and 112 controls were recruited. For descriptive study, we identified 1043 cases recorded on the line-list and for case-control study, cases were identified using national standard case-definition. Mothers of case-patients and controls were interviewed using structured questionnaire. We estimated vaccine efficacy (VE) from case-control study. We conducted bivariate and multivariable logistic regression.ResultsIn four-months period, a total of 1,043 suspected measles cases epidemiologically linked to five laboratory confirmed cases reported. Of which, 555 (53.2%) were males and 714 (68.5%) were <5 years. The median age of cases was 36 months (IQR=12-60 months). The overall attack rate (AR) was 63/10,000 population with case fatality ratio of 0.5% (5 deaths/1043). Infant <9 months were the most affected age groups (AR=31/1000). Majority (79%) of measles cases were not vaccinated against measles. Last-year (2017/18) administrative measle vaccine coverage of the district was 76.7%. Being unvaccinated against measles (AOR=5.4, 95%CI=2.2-13.4), travel history (AOR=4.02, 95%CI=1.2-13.6), contact with measles case-patient (AOR=5.6, 95%CI=2.12-14.4) and mothers knowledge of measles transmission (AOR=0.36, 95%CI=0.15-0.87) were associated with measles infection. VE in children aged 9-59 months was 90% (95%CI=69-97%).ConclusionThis confirmed measles outbreak was caused by failure to vaccinate, as indicated by the high VE, low administrative coverage, and 79% unvaccinated cases. Strengthening routine and supplementary immunization are required.