mRNA Vaccines

The concept of developing mRNA as vaccine platform evolved over the last decades. mRNA uses host cells for antigen production, can induce B and T cell responses and does not rely on unwanted antigens that may interfere with booster doses like vector vaccines. Unmodified mRNA (uRNA) may be highly reactogenic; modification results not only in improved tolerability but also increases purity and potency. While self-amplifying mRNA (saRNA) leads to higher antigen expression, such constructs are much larger, and this may reduce stability. mRNA vaccines need to be formulated in a way that allows cell entry, e.g., by using carefully designed lipid nanoparticles (LNP). As response to the COVID-19 pandemic, mRNA vaccines were developed in less than one year from receiving the genetic code to licensure. The 2 marketed and modRNA products widely used today (162b2, Pfizer/Biontech; mRNA-1273, Moderna) differ in vitro in their ability to induce a CD8 T cell response. The development of a third vaccine, based in uRNA, was recently stopped. Both licensed modRNA vaccines have an acceptable reactogenicity and safety profile, a protection rate of ≥94% in large double-blind-randomized studies in adults and children ≥12-years of age with a vaccine efficacy against symptomatic disease of >90% in the 6-month follow-up period.

Protective efficacy of 6-week regimen for latent tuberculosis infection treatment in rural China: 5-year follow-up of a randomised controlled trial

BackgroundEnlarging tuberculosis (TB) preventive treatment among at-risk populations is a critical component of the End TB Strategy. It is urgently needed to develop suitable latent tuberculosis infection (LTBI) testing and treatment tools according to local TB epidemic and available resources in worldwide.MethodsBased on an open-labeled randomised controlled trial conducted since 2015 among rural residents aged 50–70 years with LTBI, the protective efficacy of the 6-week twice-weekly regimen of rifapentine plus isoniazid was further evaluated in a 5-year follow-up survey.ResultsA total of 1298 treated participants and 1151 untreated controls were included in the 5-year protective efficacy analysis. In the per-protocol analysis, the incidence rate was 0.49/100 person-years (95% confidence interval (CI): 0.30–0.67) in the untreated control group and 0.19/100 person-years (95% CI: 0.07–0.32) in the treated group, the protection rate was 61.22%. Subgroup analysis showed that the protection rate was 76.82% in the per-protocol analysis among participants with baseline IFN-γ levels in the highest quartile (≥3.25 IU·mL−1). The multiple logistic regression analysis indicated that participants with baseline BMI <18.5 kg·m−2 and with pulmonary fibrotic lesions had increased hazard of developing active disease with an adjusted hazard ratio (aHR) of 3.64 (95% CI: 1.20–11.00) and 5.99 (95% CI: 2.20–16.27), respectively. In addition, individuals with higher baseline IFN-γ levels showed an increased risk of TB occurrence (aHR 2.27, 95% CI 1.13–4.58).ConclusionsOur findings suggested the 6-week twice-weekly regimen of rifapentine plus isoniazid for LTBI treatment might be an optional tool for TB control in Chinese population.

An Established Th2-Oriented Response to an Alum-Adjuvanted SARS-CoV-2 Subunit Vaccine Is Not Reversible by Sequential Immunization with Nucleic Acid-Adjuvanted Th1-Oriented Subunit Vaccines

A recently reported parallel preclinical study between a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine and an inactivated SARS-CoV-2 vaccine adjuvanted with alum showed pulmonary immunopathology typical of eosinophil accumulation in a mouse pneumonia model for the latter, which implied a potential role of cellular immunity in the difference in the protection rate between these two forms of vaccines. For those who have been vaccinated with alum-adjuvanted subunit or inactivated SARS-CoV-2 vaccines, whether the Th2 responses that have been established and the absence of induced cellular immunity could be changed is an open question. Using two heterologous boosts with Th1-oriented CpG ODN-adjuvanted S1-based SARS-CoV-2 subunit vaccines for mice that were primed with two doses of Th2-oriented alum-adjuvanted S1-based SARS-CoV-2 subunit vaccines, we demonstrated that established Th2 orientation could not be reversed to Th1 orientation and that no cellular immunity was induced, which should have been induced if the boosting vaccines were used as the prime vaccines. These results remind us that if widely administered alum-adjuvanted SARS-CoV-2 vaccines cannot overcome the challenge of coronavirus disease 2019 (COVID-19) and that if cellular immunity is important for the efficacy of SARS-CoV-2 vaccines in the future, the choice of more powerful heterologous boosting vaccine forms that can induce cellular immunity should be considered very carefully before application.

Assessment of Anticonvulsant Activities of Petroleum Ether Extract of Anacyclus pyrethrum Roots on Experimental Rats

Background: Epilepsy is one of the most common neurological conditions and a significant cause of morbidity and mortality. Objectives: The present study aimed to evaluate the anticonvulsant activity of the petroleum ether extract of the root of Anacyclus pyrethrum on Pentylenetetrazole (PTZ)-induced seizure model in Wistar rats. Methods: The composition of the petroleum ether extract of A. pyrethrum was first analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). Subsequently, the anticonvulsant activities of these extracts (70 and 140 mg/kg, intraperitoneal injection) were evaluated on PTZ-induced seizures in rats. The protection rate against induced seizures, latency, and duration of seizures, as well as neurological symptoms, were assessed and compared to those protected by phenobarbital. Results: GC/MS analysis of the petroleum ether extract showed that the main components were octadecadienoic acid, hexadecanoic acid, diheptylcyclopropene, naphthalene, and methyl stearate. The extract (70 and 140 mg/kg) was found to provide significant protection against PTZ-induced seizures. Moreover, compared to the negative control, the extracts increased the latency of induced-convulsion and reduced the duration of epilepsy. Interestingly, the extracts showed a reduction in neurological symptoms and the severity of seizures compared to the negative control. All of these outcomes manifested in a dose-dependent manner. Conclusion: The petroleum ether extract of A. pyrethrum may produce anticonvulsant effects by reducing the duration of seizures and delaying the latency of seizures induced by PTZ.

Immunosurveillance and molecular detection of hepatitis B virus infection amongst vaccinated children in the West Gonja District in Savanna Region of Ghana

Hepatitis B vaccination is the most effective preventive measure in reducing the incidence of chronic hepatitis B virus (HBV) infection and its consequences such as cirrhosis, hepatocellular carcinoma, liver failure and death. Ghana introduced the universal HBV vaccination in the national Expanded Programme on Immunization in 2002. The current study sought to determine the sero-protection rate and the prevalence of HBV infection among fully vaccinated children in the West Gonja District in the Savanna Region of Ghana. This cross-sectional study recruited three hundred and fifty (350) fully vaccinated children who visited West Gonja Catholic Hospital from September to December 2019 for healthcare. Structured questionnaires were administered to obtain information on the demographics. The clinical history of the participants was obtained from the hospital records. Sera were separated from 2-5ml of blood sample collected from each participant after informed consent had been sought from their parents/guardians. Sera were tested for HBsAg, anti-HBs and anti-HBc using ELISA. Samples positive for HBsAg or anti-HBc were tested for HBV DNA by Real-Time Polymerase Chain Reaction. The overall sero-protection rate (anti-HBs titers ≥ 10 mIU/mL) among the studied participants was 56% with anti-HBs geometric mean titer (GMT) of 95.7 mIU/mL (± 6.0; 95% CI) compared with GMT of 2.8 mIU/mL (± 0.2; 95% CI) among non-seroprotected participants. There was no statistically significant difference in sero-protection rate between males and females (p-value = 0.93) and in relation to age (p-value = 0.20). The prevalence of HBV infection among studied participants as determined by the HBV DNA/HBsAg positivity was 1.4% while anti-HBc sero-positivity was 2%. Even though the sero-protection rate and HBV infection rate reported in the current study compares with that of other international studies further studies need to be conducted to understand the factors related to sero-protection and HBV infection rate in the Savanna Region of Ghana.

Effectiveness of Covishield vaccine in preventing Covid–19 — A test–negative case–control study

Introduction: This study was aimed at assessing the vaccine effectiveness (VE) of Covishield, which is identical to the AstraZeneca vaccine, in preventing laboratory–confirmed Covid–19. Methods: Using a test–negative case–control design, information on vaccination status of cases with Covid–19 among healthcare workers in our institution in Puducherry, India, and an equal number of matched controls, i.e. positive and negative for SARS–CoV–2 by RT–PCR, was obtained. The cases and controls were matched for age (± 3 years) and date of testing (± 3 days). The groups were compared using multivariable conditional logistic regression to calculate odds ratios (OR), with adjustment for gender, occupational role, presence of symptoms and presence of a comorbidity condition. Per cent vaccine effectiveness (VE) was calculated as 100×(1−adjusted odds ratio). Results: Using data from 360 case–control pairs, VE of one dose and of two doses, in providing protection against Covid–19 was 49% (95% CI: 17%–68%) and 54% (27%–71%), respectively. In view of a difference in the proportion of cases and controls who had symptoms, a separate analysis of data from 203 pairs where both the case and the control had symptoms was done, which showed, VE of 58% (28%–75%) and 64% (38%–78%) after one dose and two doses, respectively. Among cases with moderately severe disease that required oxygen therapy, VE following any number of vaccine doses was 95% (44%–100%). Conclusion: Covishield vaccine protected significantly against Covid–19, with the protection after two doses being slightly higher than after one dose, and a particularly high protection rate against severe forms of the disease. Keywords: Covishield, Vaccine effectiveness, Test–negative design

Efficacy of Brucella abortus S19 and RB51 vaccine strains: a systematic review and meta-analysis

This systematic review and meta-analysis aimed to recalculate the efficacy of these two vaccine strains, and to discuss the main variables associated with controlled trials to evaluate bovine brucellosis vaccines efficacy. The most used vaccine strain was S19, at the dose of 10 colony forming units (CFU), followed by the vaccine strain RB51 at 10 CFU. The most used challenge strain was B. abortus 2308, at the dose of 10 CFU by intraconjunctival route. For the meta-analysis, trials were grouped according to the vaccine strain and dose to recalculate protection against abortion (four groups) or infection (five groups), using pooled risk ratio (RR) and vaccine efficacy (VE). For protection against abortion (n = 15 trials), S19 vaccine at 10 CFU exhibited the highest protection rate (RR = 0.25, 95% CI: 0.12 to 0.52; VE = 75.09%, 95% CI: 48.08 – 88.05), followed by RB51 10 (RR = 0.31, 95% CI: 0.16 to 0.61; VE = 69.25%, 95% CI: 39.48 – 84.38). For protection against infection (n = 23 trials), only two subgroups exhibited significant protection: S19 at 10 CFU (RR = 0.28, 95% CI: 0.14 to 0.55; VE = 72.03%, 95% CI: 57.70 – 81.50) and RB51 at 10 CFU dose (RR = 0.43, 95% CI: 0.22 to 0.84; VE = 57.05%, 95% CI: 30.90 – 73.30). In conclusion, our results suggest that the dose of 10 CFU for S19 and 10 CFU for RB51 are the most suitable for the prevention of abortion and infection caused by B. abortus.

Lactic acid bacteria that activate immune gene expression in Caenorhabditis elegans can antagonise Campylobacter jejuni infection in nematodes, chickens and mice

Background Campylobacter jejuni is the major micro-bacillary pathogen responsible for human coloenteritis. Lactic acid bacteria (LAB) have been shown to protect against Campylobacter infection. However, LAB with a good ability to inhibit the growth of C. jejuni in vitro are less effective in animals and animal models, and have the disadvantages of high cost, a long cycle, cumbersome operation and insignificant immune response indicators. Caenorhabditis elegans is increasingly used to screen probiotics for their anti-pathogenic properties. However, no research on the use of C. elegans to screen for probiotic candidates antagonistic to C. jejuni has been conducted to date. Results This study established a lifespan model of C. elegans, enabling the preselection of LAB to counter C. jejuni infection. A potential protective mechanism of LAB was identified. Some distinct LAB species offered a high level of protection to C. elegans against C. jejuni. The LAB strains with a high protection rate reduced the load of C. jejuni in C. elegans. The transcription of antibacterial peptide genes, MAPK and Daf-16 signalling pathway-related genes was elevated using the LAB isolates with a high protection rate. The reliability of the lifespan model of C. elegans was verified using mice and chickens infected with C. jejuni. Conclusions The results showed that different LAB had different abilities to protect C. elegans against C. jejuni. C. elegans provides a reliable model for researchers to screen for LAB that are antagonistic to C. jejuni on a large scale.

A Novel Running Wheel Mouse Model for Botulism and its use for the Evaluation of Post-Symptom Antitoxin Efficacy

Antitoxin is currently the only approved therapy for botulinum intoxications. The efficacy of antitoxin preparations is evaluated in animals. However, while in practice antitoxin is administered to patients only after symptom onset, in most animal studies, it is tested in relation to time post intoxication. This may be attributed to difficulties in quantitating early botulism symptoms in animals. In the current study, a novel system based on high-resolution monitoring of mouse activity on a running wheel was developed to allow evaluation of post-symptom antitoxin efficacy. The system enables automatic and remote monitoring of 48 mice simultaneously. Based on the nocturnal activity pattern of individual naïve mice, two criteria were defined as the onset of symptoms. Post-symptom treatment with a human-normalized dose of antitoxin was fully protective in mice exposed to 4 LD50 of BoNT/A and BoNT/B. Moreover, for the first time, a high protection rate was obtained in mice treated post-symptomatically, following a challenge with BoNT/E, the fastest acting BoNT. The running wheel system was further modified to develop a mouse model for the evaluation of next-generation therapeutics for progressive botulism at time points where antitoxin is not effective. Exposure of mice to 0.3 LD50 of BoNT/A resulted in long-lasting paralysis and a reduction in running activity for 16-18 days. Antitoxin treatment was no longer effective when administered 72 hr post intoxication, defining the time window to evaluate next-generation therapeutics. Altogether, the running wheel systems presented herein offer quantitative means to evaluate the efficacy of current and future anti-botulinum drugs.

P318 Intra-dermal with topical imiquimod pre-treatment versus intra-muscular hepatitis B vaccination in inflammatory bowel disease patients: a double-blind randomized controlled trial

Background Patients with inflammatory bowel disease (IBD) are often immunocompromised and at risk of various opportunistic infections including viral hepatitis. Vaccination is recommended to prevent hepatitis B infection, but efficacy with conventional intra-muscular hepatitis B vaccination in IBD patients is suboptimal. Intra-dermal vaccination has been shown to be an effective way in augmenting immune response in poor vaccine responders. In addition, topical imiquimod, a synthetic agonist of toll-like receptor 7, has been shown to further boost the immunogenicity when applied to the injection site before intra-dermal vaccination. Our study compared the efficacy of intra-dermal hepatitis B vaccination with topical imiquimod with conventional intra-muscular hepatitis B vaccination in IBD patients. Methods This is a double-blind, randomized-controlled trial. IBD patients with no evidence of active or past infection nor history of vaccination i.e. negative serology to all HBsAg/Anti-HBc/Anti-HBs were recruited. They were randomized in 1:1 ratio to receive either intra-dermal recombinant hepatitis B vaccine with topical imiquimod pre-treatment to site of injection (ID) or intra-muscular recombinant hepatitis B vaccine with topical aqueous cream (IM). Same dose (20mcg) of vaccine (Engerix B, Glaxo Smith Klein) was administered to both groups at 0, 1, 6 month. The primary outcome was the sero-protection rate at 12-month, defined as percentage of recruited subjects with anti-HBs titre ≥ 10 mIU/mL. Results 104 patients (mean age 46; 68% male; 50% Crohn’s and 50% UC) were enrolled, with 53 received ID and 51 received IM vaccine. The percentage of patients using steroids, immunomulators and biologics at the time of randomization was 15, 55 and 22 %, respectively. Baseline demographic, disease characteristic, and laboratory parameter were comparable between the ID and IM groups. Sero-protection rate at 12-month was significantly higher in the ID arm compared to the IM arm (91% vs. 69%, P=0.005; Figure). Percentage of good responders at 12 month (anti-HBs titre &gt; 100 mIU/mL) was also higher in the ID arm than in the IM (77% vs 59%, P=0.042). Multivariate analysis showed that use of ID vaccine (OR 4.45, 95% CI 1.40-14.47) and a higher albumin level (OR 1.30, 95% CI 1.06-1.58) are associated with better sero-protection rate. There was no significant difference in adverse effects reported in (64% in ID vs 55% in IM; Table). Conclusion ID hepatitis B vaccination with topical imiquimod is safe and offers superior seroprotection against hepatitis B among IBD patients.