key: cord-0814167-dva1aeip
authors: Nantanee, R.; Aikphaibul, P.; Jaru-Ampornpan, P.; Sodsai, P.; Himananto, O.; Theerawit, T.; Sophonphan, J.; Tovichayathamrong, P.; Manothummetha, K.; Laohasereekul, T.; Hiransuthikul, N.; Hirankarn, N.; Puthanakit, T.
title: Immunogenicity and reactogenicity after booster dose with AZD1222 via intradermal route among adult who had received CoronaVac
date: 2021-12-14
journal: nan
DOI: 10.1101/2021.12.12.21267695
sha: 1973ff76e36fba098f7072058e28f9c817ce0c49
doc_id: 814167
cord_uid: dva1aeip

Background Currently, booster dose is needed after 2 doses of inactivated COVID-19 vaccine. With limited resource and shortage of COVID-19 vaccine, intradermal(ID) administration might be a potential dose-sparing strategy. Objective To determine antibody response and reactogenicity of ID ChAdOx1 nCoV-19 vaccine(AZD1222,Oxford/AstraZeneca) as a booster dose after completion of 2-dose CoronaVac(SV) in healthy adult. Methods This is a prospective cohort study of adult aged 18-59 years who received 2-dose SV at 14-35 days apart for more than 2 months. Participants received ID AZD1222 at fractional low dose(1x1010 viral particles,0.1ml). Antibody responses were evaluated by surrogate virus neutralization test(sVNT) against wild type and delta variant and anti-spike-receptor-binding-domain immunoglobulin G(anti-S-RBD IgG) at prior, day14 or 28, and day90 post booster. Solicited reactogenicity was collected during 7 days post-booster. Primary endpoint was the differences of sVNT against delta strain [≥]80%inhibition at day14 and 90 compared with the parallel cohort study of 0.5-ml intramuscular(IM) route. Results From August2021, 100 adults with median(IQR) age of 46(41-52) years participated. At baseline, geometric means(GMs) of sVNT against delta strain prior to booster were 22.4%inhibition(95%CI 18.7-26.9) and of anti-S-RBD IgG were 109.3(95.4-125.1)BAU/ml. GMs of sVNT against delta strain were 92.9%inhibition(95%CI 87.7-98.3) at day14 and 73.1%inhibition(66.7-80.2) at day90 post ID booster. The differences of proportion of participants with sVNT to delta strain[≥]80%inhibition in ID recipients versus IM were +4.2%(95%CI-2.0to10.5) at day14, and -37.3%(-54.2to-20.3) at day90. Anti-S-RBD IgG GMs were 2037.1(95%CI1770.9-2343.2) at day14 and 744.6(650.1-852.9) BAU/ml at day90, respectively. Geometric mean ratios(GMRs) of anti-S-RBD IgG were 0.99(0.83-1.20) at day14, and 0.82(0.66-1.02) at day90. Only 18% reported feverish, compared with 37% of IM(p=0.003). Only 18% reported feverish, compared with 37% of IM(p=0.003). Common reactogenicity was erythema(55%) at injection site while 7% reported blister. Conclusion Low-dose ID AZD1222 booster enhanced lower neutralizing antibodies at 3 months compared with IM route. Less systemic reactogenicity occurred, but higher local reactogenicity.

73.1%inhibition(66.7-80.2) at day90 post ID booster. The differences of proportion of 75 participants with sVNT to delta strain≥80%inhibition in ID recipients versus IM were 76 +4.2%(95%CI-2.0to10.5) at day14, and -37.3% (-54.2to-20 .3) at day90. Anti-S-RBD IgG GMs 77 were 2037.1(95%CI1770.9-2343.2) at day14 and 744.6(650.1-852.9) BAU/ml at day90, 78 respectively. Geometric mean ratios(GMRs) of anti-S-RBD IgG were 0.99(0.83-1.20) at day14, 79 and 0.82(0.66-1.02) at day90. Only 18% reported feverish, compared with 37% of IM(p=0.003). 80

Only 18% reported feverish, compared with 37% of IM(p=0.003). Common reactogenicity was 81 erythema(55%) at injection site while 7% reported blister. 82

Low-dose ID AZD1222 booster enhanced lower neutralizing antibodies at 3 months compared 84 with IM route. Less systemic reactogenicity occurred, but higher local reactogenicity. Calmette-Guerin (BCG), and polio vaccination [7, [9] [10] [11] [12] . For influenza vaccine, a systematic 124 review and meta-analysis showed comparable seroprotection rates for 9-µg ID with 15-µg IM 125 injection with higher local adverse event particularly erythema and swelling [ This study aims to evaluate immunogenicity and reactogenicity of ID AZD1222 booster 138 dose in adults who had received 2 doses of CoronaVac. 139 140 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

All participants' samples were tested for spike receptor binding domain (NIBSC 20/136). We used anti-S-RBD IgG level at 506 BAU/ml, which is correlated with 80% 185 vaccine efficacy reported by the Oxford COVID vaccine trial group [17], as a cut off. 186 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

For T cell, ELISpot assay using a Human IFN-γ ELISpotPro TM kit (Mabtech, Stockholm, R848 and IL-2 for 72 hours. Unstimulated well was also used as negative control. Stimulated and 208 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ; https://doi.org/10.1101/2021.12.12.21267695 doi: medRxiv preprint unstimulated PBMCs (5 × 10 5 cells per well) were added into ELISpot plate and incubated for 209 18 hours. An RBD-WASP antigen was added into RBD-specific IgG detected well while 210 MT78/145-biotinylated antibodies were added into total IgG detected well, positive control. 211

Anti-WASP-ALP was added into RBD-specific IgG detected well and negative control well 212 while streptavidin-ALP was added into total IgG detected well. Spot counting was performed in 213 the same method as T cells. 214 215

Solicited reactogenicity was recorded by participants using diary. All symptoms were 217 graded in 3 grades [19]: grade 0 for no symptom; grade 1 for mild symptom, which was not 218 interfere with activities or vomiting 1 -2 times/day or diarrhea 2 -3 times/day; grade 2 for 219 moderate symptom, which interfered with activities or need to take medication, or vomiting 220 more than 2 times/day or diarrhea 4 -5 times/day; grade 3 for severe symptom, which 221 incapacitated or need hospitalization or diarrhea 6 or more times/day. Fever was graded as grade were assessed using a Wilcoxon rank sum test, Chi-square test, or fisher exact test, respectively. 230

The sVNT results, to either wild type or delta strain, of more than 80% were used to classify the 231 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ; https://doi.org/10.1101/2021.12.12.21267695 doi: medRxiv preprint achievement of 80% protection against symptomatic infection. The anti-S-RBD IgG of more 232 than 506 BAU/ml were used in this study as a cut off for protective antibody level, which 233 previously reported to be associated with 80% vaccine efficacy against primary symptomatic 234

We presented primary comparisons between ID and IM group in terms of the differences of 236 proportion of participants achieving sVNT preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. booster, as shown in Figure 2 and 

The GMs Table 2 . 282 283

Proportion of participants with sVNT to delta strain ≥ 80% inhibition at day 14 was non-inferior 285 among ID recipients compared with IM recipients, with difference of 4.2% (95% CI -2.0 to 286 10.5). But at day 90, it was significantly lower, with difference of -37.3% (-54.2 to -20.3). These 287 differences were similar to sVNT to wild type, as shown in Table 2 . GMR of anti-S-RBD IgG 288 showed non-inferiority at day14, with GMR of 0.99 (0.83-1.20), and borderline inferior at day 289 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

From the sub study analysis of CMI response, ELISpot assay showed significant rise of T 294 cell and B cell response at day 28 and declined at day 90, as shown in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ; https://doi.org/10.1101/2021.12.12.21267695 doi: medRxiv preprint 4. Discussion 304 ID AZD1222 booster vaccine in 2-dose-CoronaVac-primed adults raised high anti-S-305 RBD IgG >506 BAU/ml, and high levels of functional neutralizing antibodies >80% inhibition 306 as measured by sVNT to wild type and delta strain, thus non-inferior to IM route at day 14. 307 However, at 3 months post ID AZD1222 booster vaccination, this study demonstrated, despite 308 similar anti-S-RBD IgG, but lower sVNT against delta strain to IM booster, suggesting more 309 rapid waning neutralizing antibody response after ID compared to IM route. Most reactogenicity 310 occurred locally with erythema, pain, and swelling at injection site. Erythema, swelling, and 311 blister were reported more common in ID booster. Systemic symptoms such as fever, feverish, 312 headache, fatigue, and myalgia were less common than conventional IM injection. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This study reported local reactogenicity including erythema, blister, and pruritus after ID 338 AZD1222 booster vaccine which is similar to previous report on rabies inactivated vaccine that 339 more erythema and pruritus were reported from ID than conventional IM administration [28] . 340 Also blister formation was reported after BCG vaccination that evolved over two weeks into an 341 ulcer at injection site [29] . ID influenza vaccine study reported significant higher local adverse 342 events particularly erythema and swelling, and also more common of fever and chills which is 343 different from this study that fever was more common in IM vaccination [9] . Hyperpigmentation 344 was also reported in this study as still seen on day 28 follow up visit which previous study of 345 hepatitis B vaccine reported of local hyperpigmentation after ID vaccination in 55% [30] . 346

Compared with parallel cohort IM study, ID booster had more local reactogenicity feverish, arthralgia and diarrhea). 349 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This study was limited by cohort study design without randomized control trial but there 360 was the parallel cohort study with similar setting that should be able to benchmark the results. 361

There were 2 factors that differed between the 2 groups. Specifically, there was more male in the 362 ID group and the time interval between second and third dose was 1 week longer in the ID 363 group. However, the immune responses at baseline before the third dose were comparable. 364

Female was reported to have higher antibody response to vaccines [37] and after severe COVID-365

19 [38] . The finding of later inferior neutralizing antibodies might be attributed to this gender 366 difference, specifically more male participants in ID cohort. This study chose to determine the 367 levels of functional neutralizing antibodies using the surrogate virus neutralization assay, rather 368 than standard live-virus neutralization assay. However, we used the high cut-off value at 80% of 369 sVNT in this study. Moreover, good correlations between sVNT and live-virus neutralization 370 have been exhibited elsewhere [18, [39] [40] [41] . The strengths of this study were reporting complete 371 solicited reactogenicity of all 100 participants with ID booster vaccination and multiple methods 372 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ;

were used for immunity analysis including anti-S-RBD, sVNT ( wild type and delta strain) and 373 also CMI responses. 374

Intradermal AZD1222 booster vaccine in 2-dose-CoronaVac primed adult enhanced 375 comparable short-term immunity, but inferior 3-month immunogenicity, with intramuscular 376 administration. Reactogenicity was usually localized ( erythema and pain) and less systemic than 377 intramuscular vaccine. Due to more rapid waning neutralizing antibody, dose-sparing strategy 378 with intradermal booster vaccination should be used in the setting of inadequate vaccine supply. 379 380 381 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ; https://doi.org/10.1101/2021.12.12.21267695 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ; preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ; https://doi.org/10.1101/2021.12.12.21267695 doi: medRxiv preprint hyperpigmented macule and iv) erythematous patch at injection site at day 28 and (B) a serial 469 photography day 1-7 in single participant: Day 1 erythematous patch at injection site, Day 2 470 central swelling on erythematous patch, Day 3-6 blister forming at central of erythematous patch, 471 and Day 7 dry blister with necrotic crust on erythematous base. 472 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 14, 2021. ; https://doi.org/10.1101/2021.12.12.21267695 doi: medRxiv preprint

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