Immunogenicity and reactogenicity of mRNA COVID-19 vaccine booster administered by intradermal or intramuscular route in Thai older adults (preprint)

Introduction: Intradermal (ID) vaccination may alleviate COVID-19 vaccine shortages and vaccine hesitancy due to systemic reactogenicity among older adults. Objectives: To compare the immunogenicity and reactogenicity of fractional ID and standard intramuscular (IM) booster vaccination of mRNA-1273 and BNT162b2 vaccines in older adults. Methods: Participants aged [≥]65 years who previously vaccinated with 2-dose ChAdOx1 were randomized to receive one of the four booster vaccinations: 0.1mL ID mRNA-1273, 0.5mL IM mRNA-1273, 0.1mL ID BNT162b2 and 0.3mL IM BNT162b2. Immunogenicity as measured by anti-receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NAb) against Wuhan and Omicron BA.1, BA.2 and BA.4/5, and IFN{gamma}-producing cells. Local and systemic adverse effects (AEs) were self-reported via an electronic diary card. Results: Of the 210 participants enrolled, 70.5% were female and median age was 77.5 years (interquartile range (IQR): 71.0-84.0). Following the booster dose, both ID vaccination induced 37% lower levels of anti-RBD IgG than IM vaccination of the same vaccine. NAb against ancestral and Omicron BA.1 strains was highest following IM mRNA-1273 (1,718 and 617), followed by ID mRNA-1273 (1,212 and 318), IM BNT162b2 (713 and 230), and ID BNT162b2 (587 and 148), respectively. Spike-specific IFN{gamma} responses were similar or higher in the ID groups when compared with their respective IM groups. Vaccine delivery through ID route tended to have lower systemic AEs, although more local AEs reported in ID mRNA-1273 group. Conclusions: Fractional ID vaccination induced immunogenicity and reactogenicity comparable to IM and may be an alternative option for older people.

Immune responses of the third dose of AZD1222 vaccine or BNT162b2 mRNA vaccine after two doses of CoronaVac vaccines against Delta and Omicron variants (preprint)

Summary. Half-dose AZD1222 or BNT162b2 boosters maintained immunogenicity and safety, and were non-inferior to full doses. All doses elicited high immunogenicity and best with extended post-CoronaVac primary-series intervals (120-180 days) and high-transmissibility Omicron. Methods. At 60-to-<90, 90-to-<120, or 120-to-180 days (intervals) post-CoronaVac primary-series, participants were randomized to full-dose or half-dose AZD1222 or BNT162b2, and followed up at day-28, -60 and -90. Vaccination-induced immunogenicity to Ancestral, Delta and Omicron BA.1 strains were evaluated by assessing anti-spike (anti-S), anti-nucleocapsid antibodies, pseudovirus neutralization (PVNT), micro-neutralization titers, and T-cells assays. Descriptive statistics and non-inferiority cut-offs were reported as geometric mean concentration (GMC) or titer (GMT) and GMC/GMT ratios comparing baseline to day-28 and day-90 seroresponses, and different intervals post-CoronaVac primary-series. Omicron immunogenicity was only evaluated in full-dose recipients. Findings. No serious or severe vaccine-related safety events occurred. All assays and intervals showed non-inferior immunogenicity between full-doses and half-doses. However, full-dose vaccines and/or longer, 120-to-180-day intervals substantially improved immunogenicity (in GMC measured by anti-S assays or GMT measured by PVNT50; p <0.001). Within platforms and regardless of dose or platform, seroconversions were over 97%, and over 90% for pseudovirus neutralizing antibodies, but similar against the SARS-CoV-2 strains. Immunogenicity waned more quickly with half-doses than full-doses between day 60-to-90 follow-ups, but remained high against Ancestral or Delta strains. Against Omicron, the day-28 immunogenicity increased with longer intervals than shorter intervals for full-dose vaccines. Interpretation. Combining heterologous schedules, fractional dosing, and extended post-second dose intervals, broadens population-level protection and prevents disruptions, especially in resource-limited settings. Funding. Funding was provided by the Program Management Unit for Competitiveness Enhancement (PMU-C) National research, National Higher Education, Science, Research and Innovation Policy Council, Thailand through Clinixir Ltd.

Safety and Immunogenicity of Intradermal Administration of Fractional Dose CoronaVac(R), ChAdOx1 nCoV-19 and BNT162b2 as Primary Series Vaccination (preprint)

There is a limited supply of COVID-19 vaccines, with less than 20% of eligible populations in low- income countries having received one dose. Intradermal delivery of fractional dose vaccines is one way to improve global vaccine access, but no studies have reported data on intradermal delivery of COVID-19 primary series vaccination. We conducted a pilot study to examine the safety and immunogenicity of three intradermal primary series regimens - heterologous regimen of CoronaVac and ChAdOx1 (CoronaVac-ChAdOx1), homologous regimen of ChAdOx1 (ChAdOx1-ChAdOx1), and homologous regimen of BNT162b2 (BNT162b2-BNT162b2). Each dose was 1/5th or 1/6th of the standard dose. Two additional exploratory arms of intradermal vaccination for the second dose following an intramuscular first dose of ChAdOx1 and BNT162b2 were included. Intradermal vaccination was found to be immunogenic and safe. The antibody responses generated by the intradermal primary series were highest in the BNT162b2 arms. The anti-receptor binding domain (anti-RBD) IgG concentration following fractional dose intradermal vaccination was similar to that of standard dose intramuscular vaccination of the same regimen, except for BNT162b2. The BNT162b2 intradermal series generated a lower antibody concentration than the reference intramuscular series, despite generating the highest antibody concentration of all three intradermal primary series regimens. Neutralizing antibody responses against the SARS-CoV-2 ancestral strain were consistent with what was observed for anti-RBD IgG, with lower titers for SARS-CoV-2 variants. The FRNT50 titers were lowest against the omicron variant, being undetectable (GMT[≤]10) in about a quarter of study participants. T-cell responses against spike- and nucleocapsid-membrane-open reading frame proteins were also detected following intradermal vaccination. Adverse effects following intradermal vaccination were generally comparable with post-intramuscular vaccination effects. Taken together, our data suggest that intradermal vaccination using 1/5th or 1/6th of standard COVID-19 intramuscular vaccination dosing generates similar immune responses with tendency of lower systemic adverse reactions than intramuscular vaccination. Our findings have implications in settings where COVID-19 vaccines are in shortage.

Evaluation of the safety and immunogenicity of fractional intradermal COVID-19 vaccines as a booster: A pilot study (preprint)

Intradermal vaccination using fractional dosage of the standard vaccine dose is one strategy to improve access to COVID-19 immunization. We conducted a pilot study in healthy adults in Thailand to evaluate the safety and immunogenicity of intradermal administration of fractional dose of ChAdOx1 (1/5th of standard dosage) or BNT162b2 (1/6th of standard dosage) to individuals previously vaccinated (prime) with two-dose intramuscular CoronaVac, ChAdOx1 or BNT162b2. Following an initial immunogenicity exploratory phase for each vaccine combination group (N=10), a total of 135 participants (N=45 per group) were recruited to three groups (CoronaVac prime-intradermal BNT162b2 boost, CoronaVac prime-intradermal ChAdOx1 boost and ChAdOx1 prime-intradermal BNT162b2 boost) and their immunogenicity data compared to a previous cohort who received the same vaccine intramuscularly. Two weeks following booster vaccination, neutralizing antibodies against the delta variant were similar between intradermal and intramuscular vaccination. However, neutralizing antibodies against the omicron variant in the intradermal BNT162b2 boost groups were [~]6-fold lower, while the ChAdOx1 boost group was [~]5-fold higher compared to their respective vaccine regimen given intramuscularly. The intradermal booster significantly increased spike-specific T cell responses in all three groups from pre-booster levels. Local and systemic adverse reactions were milder in intradermal compared to intramuscular injections. Further studies are needed to evaluate the clinical relevance of these findings and the feasibility of administration of intradermal COVID-19 vaccines.

Early Treatment of Favipiravir in COVID-19 Patients Without Pneumonia: A Multicentre, Open-Labelled, Randomized Control Study (preprint)

We investigated Favipiravir (FPV) efficacy in mild cases of COVID-19 without pneumonia and its effects towards viral clearance, clinical condition, and risk of COVID-19 pneumonia development. PCR-confirmed SARS-CoV-2-infected patients without pneumonia were enrolled (2:1) within 10 days of symptomatic onset into FPV and control arms. The former received 1800 mg FPV twice-daily (BID) on Day 1 and 800 mg BID 5-14 days thereafter until negative viral detection, while the latter received supportive care only. The primary endpoint was time to clinical improvement, which was defined by a reduced National Early Warning Score (NEWS) or score of <1. 62 patients (41 female) comprised the FPV arm (median age: 32 years, median BMI: 22 kg/m2) and 31 patients (19 female) comprised the control arm (median age: 28 years, median BMI: 22 kg/m2). The median time to sustained clinical improvement by NEWS was 2 vs 14 days for FPV and control arms respectively (adjusted hazard ratio (aHR) of 2.77, 95% CI 1.57-4.88, P <0.001). The FPV arm also had significantly higher likelihoods of clinical improvement within 14 days after enrolment by NEWS (79% vs 32% respectively, P <0.001), particularly female patients (aOR 6.35, 95% CI 1.49-27.07, P <0.001). 8 (12.9%) and 7 (22.6%) patients in FPV and control arms developed mild pneumonia at a median (range) 6.5 (1-13) and 7 (1-13) days after treatment, respectively (P = 0.316); all recovered well without complications. We can conclude that early treatment of FPV in symptomatic COVID-19 patients without pneumonia was associated with faster clinical improvement.

Pharmacokinetics of favipiravir in adults with mild COVID-19 in Thailand (preprint)

We assessed the pharmacokinetics of favipiravir (FPV) in adults with symptomatic SARS-CoV-2 infection without pneumonia in Thailand. FPV dosing was 1800 mg twice-daily on day 1, then 800 mg twice-daily for 14 days. Eight subjects (7 female), median (range) age 39 (19-53) years and BMI 27.9 (18.0-33.6) were included. Inter-subject variability was high but all achieved minimum plasma concentrations (Cmin) above EC50 (9.7 mg/L). FPV was well tolerated; 1 subject stopped prematurely due to rash.

Immunogenicity and reactogenicity against the SARS-CoV-2 variants following heterologous primary series involving CoronaVac and ChAdOx1 and BNT162b2 plus heterologous BNT162b2 booster vaccination: An open-label randomized study in healthy Thai adults. (preprint)

We evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary series vaccination schedules. Participants were randomized to one of seven groups that received two-dose homologous BNT162b2 or heterologous combinations of CoronaVac, ChAdOx1 and BNT162b2, with 4 weeks interval. Of 210 participants, median age was 38 (19-60) years, 51% were female. The groups that received BNT162b2 as second dose induced the highest virus-specific IgG response against the ancestral strain [BNT162b2: geometric mean concentration (GMC) 2133-2249, 95%CI 1558 to 3055; ChAdOx1: 851-1201, 95%CI 649 to 1522; CoronaVac: 137-225, 95%CI 103-286 BAU/mL], neutralising antibodies (NAb) against Beta and Delta, and interferon gamma response. All groups induced low to negligible NAb against Omicron. A BNT162b2 booster (3rd dose) following heterologous CoronaVac and ChAdOx1 regimens induced >140-fold increase in NAb titres against Omicron. Our findings indicate that heterologous regimens using BNT162b2 as the second dose may be considered an alternative schedule to maximize immune response.

The immunogenicity and safety of different COVID-19 booster vaccination following CoronaVac or ChAdOx1 nCoV-19 primary series (preprint)

The appropriate COVID-19 booster vaccine following inactivated or adenoviral vector COVID-19 vaccination is unclear. We evaluated the safety and immunogenicity of different booster vaccines, inactivated (BBIBP-CorV), chimpanzee adenoviral vector (ChAdOx1), or mRNA (BNT162b2 at full (30 µg), or half (15 µg) dose) in healthy adults who received 2-dose primary series of either inactivated vaccine (CoronaVac) or ChAdOx1 8-12 weeks earlier. Overall, the adverse events for all booster vaccines were mild and moderate. Two weeks post-booster dose, the neutralising antibody titres against Delta variant in CoronaVac-prime and ChAdOx1-prime were highest with for 30µg-BNT162b2 (411 vs 470) and 15µg-BNT162b2 (499 vs 358); followed by ChAdOx1 (271 vs 69), and BBIBP-CorV (61.3 vs 49). BNT162b2 also induced higher interferon gamma response. Heterologous COVID-19 boosting vaccination with BNT162b2 is the most immunogenic following CoronaVac or ChAdOx1 primary series. A lower dose BNT162b2 may be used as booster in settings with limited vaccine supply.

The immunogenicity and safety of different COVID-19 booster vaccination following CoronaVac or ChAdOx1 nCoV-19 primary series (preprint)

The appropriate COVID-19 booster vaccine following inactivated or adenoviral vector COVID-19 vaccination is unclear. We evaluated the safety and immunogenicity of different booster vaccines, inactivated (BBIBP-CorV), chimpanzee adenoviral vector (ChAdOx1), or mRNA (BNT162b2 at full (30 g), or half (15 g) dose) in healthy adults who received 2-dose primary series of either inactivated vaccine (CoronaVac) or ChAdOx1 8-12 weeks earlier. Overall, the adverse events for all booster vaccines were mild and moderate. Two weeks post-booster dose, the neutralising antibody titres against Delta variant in CoronaVac-prime and ChAdOx1-prime were highest with for 30g-BNT162b2 (411 vs 470) and 15g-BNT162b2 (499 vs 358); followed by ChAdOx1 (271 vs 69), and BBIBP-CorV (61.3 vs 49). BNT162b2 also induced higher interferon gamma response. Heterologous COVID-19 boosting vaccination with BNT162b2 is the most immunogenic following CoronaVac or ChAdOx1 primary series. A lower dose BNT162b2 may be used as booster in settings with limited vaccine supply.

Safety and Immunogenicity of CoronaVac and ChAdOx1 Against the SARS-CoV-2 Circulating Variants of Concern (Alpha, Delta, Beta) in Thai Healthcare Workers (preprint)

Importance: Inactivated vaccine (CoronaVac) and chimpanzee adenovirus-vector vaccine (ChAdOx1) have been more available in resource-limited settings. However, the data comparing between these two vaccines in the same setting are limited. Objectives: To determine adverse events (AEs) and immunogenicity of CoronaVac and ChAdOx1 in health care workers (HCWs). Design: This prospective study was conducted from February to July 2021. Setting: A single center, university-based tertiary care center in Bangkok. Participants: Healthy HCWs. Exposure: Two doses of CoronaVac (4 weeks apart) or ChAdOx1 (8 weeks apart) intramuscularly. Main Outcomes and Measures: Self-reported AEs were collected for 7 days following each vaccination using electronic diary. The immunogenicity was determined by the level of IgG antibodies against receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S1 subunit). The 50% plaque reduction neutralization tests against original Wuhan strain and circulating VOCs were performed in subset of samples at 2 weeks after the second dose. Results: Of the 360 HCWs, 180 received each vaccine. The median (interquartile range: IQR) age was 35 (29-44) years old and 84.2% were female. Participants who received ChAdOx1 reported higher frequency of AEs than those received CoronaVac after both the first dose (84.4% vs. 66.1%, P < 0.001) and second dose (75.6% vs. 60.6%, P = 0.002), with more AEs in those younger than 30 years of age for both vaccines. The seroconversion rate was 75.6% and 100% following the first dose of CoronaVac and ChAdOx1, respectively. All participants seroconverted at 2 weeks after the second dose. The anti-SARS-CoV-2 RBD IgG levels induced by CoronaVac was lower than ChAdOX1 with geometric means of 164.4 and 278.5 BAU/mL, respectively (P = 0.0066). Both vaccines induced similar levels of neutralizing antibodies against the Wuhan strain, geometric mean titer (GMT) of 337.4 vs 331.2; however, CoronaVac induced significantly lower GMT against Alpha (23.1 vs. 92.5), Delta (21.2 vs. 69.7), and Beta (10.2 vs. 43.6) variants, respectively. Conclusions and Relevance: CoronaVac induces lower measurable antibodies but with lower frequency of AEs than ChAdOx1. The low neutralizing antibodies against the circulating VOCs induced by CoronaVac supports the need for earlier boosting to prevent breakthrough infections. Trial Registration: TCTR20210720002 https://www.thaiclinicaltrials.org/