{"id":49664,"date":"2023-06-30T11:40:31","date_gmt":"2023-06-30T11:40:31","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=49664"},"modified":"2023-07-11T05:48:34","modified_gmt":"2023-07-11T05:48:34","slug":"s-rbd-antibody-titers-following-the-first-and-second-doses-of-inactivated-sars-cov-2-vaccination-coronavac-in-native-participants-a-prospective-cohort-study-in-bali-indonesia","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no2\/s-rbd-antibody-titers-following-the-first-and-second-doses-of-inactivated-sars-cov-2-vaccination-coronavac-in-native-participants-a-prospective-cohort-study-in-bali-indonesia\/","title":{"rendered":"S-RBD Antibody Titers Following the First and Second Doses of Inactivated SARS-CoV-2 Vaccination (CoronaVac) in Native Participants: A Prospective Cohort Study in Bali, Indonesia"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Coronavirus disease 2019 (COVID-19) caused\nby severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted\nthe lives of individuals worldwide.1,\n2<\/sup> Types\nof COVID-19 vaccines have been developed and entered clinical trials, with some\nhave received the approval to be used in the community.3<\/sup> In\naddition, several oral therapies such as molnupiravir and ritonavir-boosted\nnirmatrelvir which are thought to turn the tide of the pandemic are currently\nunder investigation in clinical trials.4,\n5<\/sup> With\nvaccination program along with improved healthcare capacity and the enforcement\nof COVID-19 prevention protocols, the end of the pandemic has been predicted\nwith multiple scenarios.6<\/sup> Nonetheless, the challenge of controlling the SARS-CoV-2 infection still\nremains as it shift into endemic state.6<\/sup> Moreover, several countries face vaccine hesitancy issues which are\nassociated with the perceived efficacy and side effects.7,\n8<\/sup>\nTherefore, monitoring vaccine efficacy in inducing the immune system and its\nadverse reactions is important.<\/p>\n\n\n\n

Among 11 vaccines approved in Indonesia, the one commonly administered is an inactivated whole-virion SARS-CoV-2 vaccine, CoronaVac, developed by Sinovac Life Sciences (Beijing, China).9<\/sup> The vaccine is based on inactivated SARS-CoV-2 (CZ02 strain) and added with aluminum hydroxide as its adjuvant.3, 10<\/sup> One of the most significant features of this vaccine is its easy transportation after freeze-dried and only require 2\u20148\u00b0C storing temperatures.11<\/sup> In terms of its efficacy, a phase 3 placebo-controlled clinical trial from Turkey revealed two doses of CoronaVac injection reached 83.5% against PCR-confirmed symptomatic COVID-19, where no serious adverse reactions were observed.12<\/sup> The efficacy, however, was found lower (50.7%) in a clinical trial among Brazilian healthcare professionals.13<\/sup> In Chile, the vaccine efficacy to prevent the infection was 65.9%, hospitalization  87.5%, ICU admission 90.3%, and mortality 86.3%.14<\/sup><\/p>\n\n\n\n

To investigate\nvaccine efficacy, levels of antibody such as anti-spike receptor-binding domain\n(S-RBD) antibody could be used as it correlates with symptomatic COVID-19\nincidence.15,\n16<\/sup> Spike\nprotein of SARS-CoV-2 RBD is responsible for the viral entry through\nangiotensin-converting enzyme 2 (ACE2) and it could induce the neutralizing\nantibodies.17<\/sup> A\nsingle dose of CoronaVac  (3 \u03bcg) among\nChinese population (18-59 years old) yield 92% seroconversion for neutralizing\nantibodies on day 14 and 97% on day 28.15<\/sup> Meanwhile, in Chilean population (n=397, 18\u201459 years old), two\ndoses of CoronaVac resulted in 86.67% seroconversion for anti-S-RBD IgG.18<\/sup>\nDespite data have been gathered around the world regarding the vaccine\nefficacy, studies in Bali, province a tourism hotspot in Indonesia with high\nair travel frequency, are scarcely reported.19<\/sup> Herein, we present data on the CoronaVac immunogenicity and its\nadverse reaction following the first and second vaccinations among Balinese\npopulation. <\/p>\n\n\n\n

Methods<\/strong><\/p>\n\n\n\n

Study design<\/strong><\/p>\n\n\n\n

A prospective cohort study involving 422\nBalinese volunteers was conducted between July 10th<\/sup> and December 30th<\/sup>,\n2021 to identify the immunogenicity of the inactivated virus vaccine (Sinovac\nBiotech, CoronaVac). One hundred and seventy-two healthy subjects were\nrecruited based on the data provided by the three vaccination centers in Bali.\nBlood samples were collected three times on each individual: before the\nvaccination and after the first and second shots, respectively. <\/p>\n\n\n\n

Recruitment and sampling<\/strong><\/p>\n\n\n\n

Volunteers (n=422) were recruited from the\nvaccination centers in Bali Province, Indonesia, from July 10th<\/sup> to\nDecember 30th<\/sup>, 2021. Individuals aged \u226518 years old were considered\neligible. Data of age, gender, body mass index (BMI), and side effects of the\nvaccination were collected. BMI was measured from the length and body weight of\neach volunteer. For each time, three mL of venous blood samples from\nparticipant was collected and centrifuged to separate the sera. Blood sampling\nwas performed three times: pre-vaccination, 21-days post-1st<\/sup> shot\nand 56-days post-2nd<\/sup> shot. The interval between the 1st<\/sup>\nand 2nd<\/sup> shot was 28 days. <\/p>\n\n\n\n

The S-RBD titer of the pre-vaccination\nblood samples was measure and those who were seropositive were excluded from\nthe study. Participants who did not return after the first sampling or\nconfirmed SARS-CoV-2 positive based on the real-time quantitative reverse\ntranscription-polymerase chain reaction (RT-PCR) were dropped out from the\nstudy. A schematic diagram depicting how the participants were included in this\nstudy is presented in Figure 1.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Sampling flowchart<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Electrochemiluminescence immunoassay (ECLIA)<\/strong><\/p>\n\n\n\n

All sera were analyzed with electrochemiluminescence immunoassay (ECLIA) using Elecsys\u00ae anti-SARS-CoV-2 S quantitative assay kit (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) to determine the total anti S-RBD neutralizing antibody titer. The analysis was carried out on automatic Roche cobas\u00ae e601 immunoassay analyzer (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). A double-antigen sandwich assay approach was used by the system utilizing recombinant protein representing the RBD of the S antigen. The analysis was conducted following the manufacturers\u2019 instruction. The detectable antibody titer ranged between 0.4 U\/mL and 250 U\/mL and a titer of \u2265 0.8 U\/mL was classified as positive possessing antibody against SARS-CoV-2 S-RBD. <\/p>\n\n\n\n

Statistical analysis<\/strong><\/p>\n\n\n\n

SPSS\nVersion 25 (SPSS Inc., Chicago, IL) was used to statistically analyses the data\nthat were collected. A probability value of P \u2264 0.05 was considered statistically\nsignificant. Repeated ANOVA or Friedman test was used as\ncomparison analysis according to data distribution. If there were significant\ndifferences, subsequent post hoc analysis using paired wise comparison or\nWilcoxon test was done.<\/p>\n\n\n\n

Ethical clearance <\/strong><\/p>\n\n\n\n

Ethical clearance for this study obtained\nfrom the Ethical Committee of the Faculty of Medicine and Health Sciences,\nUniversitas Warmadewa on 8 July 2021 (68\/Unwar\/FKIK\/EC-KEPK\/VII\/2021). A\nwritten informed consent was obtained from all volunteers.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Characteristics of the subjects and vaccine reactogenicity<\/strong><\/p>\n\n\n\n

Characteristics of volunteers participating\nin this study are presented in Table 1. Most of the volunteers were \u2264 29 years\nold (65\/172, 37.8%) and male (124\/172, 60.5%) with mean BMI of 23.19 \u00b1 4.45.\nSystemic adverse reactions experienced by the participants after the first\nvaccination included fever (8\/172, 4.7%), sleepiness (2\/172, 1.2%), dizziness\n(2\/172, 1.2%), hunger (1\/172, 0.6%), and weakness (1\/172, 0.6%), whilst 2.9%\n(5\/172) volunteers experienced the injection-site pain. As many as 153 (89%)\nvolunteers did not experience any adverse reaction. On second vaccination, the\nnumber of adverse reactions dramatically reduced to almost none (only 1\nvolunteer felt hunger after the second shot). <\/p>\n\n\n\n

Table 1: Demographics data of the subjects and vaccination side effects (n=172)<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Variables<\/strong><\/p>\n<\/td>\n

\n

n (%)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Age, years old<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

\u2264 29<\/p>\n<\/td>\n

\n

65 (37.8)<\/p>\n<\/td>\n<\/tr>\n

\n

30-39<\/p>\n<\/td>\n

\n

41 (23.8)<\/p>\n<\/td>\n<\/tr>\n

\n

40-49<\/p>\n<\/td>\n

\n

31 (18)<\/p>\n<\/td>\n<\/tr>\n

\n

50-59<\/p>\n<\/td>\n

\n

20 (11.6)<\/p>\n<\/td>\n<\/tr>\n

\n

>59<\/p>\n<\/td>\n

\n

15 (8.7)<\/p>\n<\/td>\n<\/tr>\n

\n

Gender<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Male<\/p>\n<\/td>\n

\n

124 (60.5)<\/p>\n<\/td>\n<\/tr>\n

\n

Female<\/p>\n<\/td>\n

\n

48 (39.5)<\/p>\n<\/td>\n<\/tr>\n

\n

Body mass index, mean \u00b1 SD<\/p>\n<\/td>\n

\n

23.19 \u00b1 4.45<\/p>\n<\/td>\n<\/tr>\n

\n

Vaccination side effect<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

1st<\/sup> dose vaccination<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

No side effect<\/p>\n<\/td>\n

\n

153 (89.0)<\/p>\n<\/td>\n<\/tr>\n

\n

Fever<\/p>\n<\/td>\n

\n

8 (4.7)<\/p>\n<\/td>\n<\/tr>\n

\n

Injection-site pain<\/p>\n<\/td>\n

\n

5 (2.9)<\/p>\n<\/td>\n<\/tr>\n

\n

Sleepiness<\/p>\n<\/td>\n

\n

2 (1.2)<\/p>\n<\/td>\n<\/tr>\n

\n

Dizziness<\/p>\n<\/td>\n

\n

2 (1.2)<\/p>\n<\/td>\n<\/tr>\n

\n

Hunger<\/p>\n<\/td>\n

\n

1 (0.6)<\/p>\n<\/td>\n<\/tr>\n

\n

Weakness<\/p>\n<\/td>\n

\n

1 (0.6)<\/p>\n<\/td>\n<\/tr>\n

\n

2nd<\/sup> dose vaccination<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

No side effect<\/p>\n<\/td>\n

\n

171 (99.4)<\/p>\n<\/td>\n<\/tr>\n

\n

Hunger<\/p>\n<\/td>\n

\n

1 (0.6)<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

S-RBD antibody titers post CoronaVac vaccination<\/strong><\/p>\n\n\n\n

S-RBD titers of each volunteer were measured before and after the first and second dose. All volunteers were seronegative before the vaccination and more than half became seropositive 21 days after first dose. The mean antibody titers at 21 days after the first dose of CoronaVac was 25.25 \u00b1 59.74 U\/mL. The mean titers increased to 138.77 \u00b1 90.93 U\/mL 56 days after the second dose. Seroconversion rate 21 days after the first dose of CoronaVac was 69.7% (120\/172) and increased to 99.4% (171\/172) 56 days after the second dose. Only one patient was still seronegative after second dose of CoronaVac. <\/p>\n\n\n\n

The study analyzes the titers of anti-S-RBD\npre-vaccine, at 21 days after first dose and 56 days after second dose\nvaccination. Statistical\nanalysis showed that the data distribution was not normal p<\/em> <0.05 and\nFriedman test was used to compared anti-S-RBD levels before, and after the\nfirst and second vaccination. The results reveal the\ntiters of anti S-RBD were significantly difference among the three-testing\npoint (Table 2). The Friedman test result was p<\/em> <0.001 which means\nthat there are significant differences of anti-S-RBD levels in at least at\ntwo-testing point.<\/p>\n\n\n\n

Table 2: Friedman test of anti-S-RBD IgG levels in each testing point<\/strong><\/p>\n\n\n\n\n\n\n\n\n
\n

Anti S-RBD IgG level (U\/ml)<\/strong><\/p>\n<\/td>\n

\n

n<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n

\n

Mean<\/strong><\/p>\n<\/td>\n

\n

p<\/em><\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Pre vaccination<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

< 0.001<\/p>\n<\/td>\n<\/tr>\n

\n

21 days after 1st<\/sup> dose<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

2.7 (0-251)<\/p>\n<\/td>\n

\n

25.25 \u00b1 59.74<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

56 days after 2n<\/sup>d<\/sup> dose<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

128 (0-251)<\/p>\n<\/td>\n

\n

138.77 \u00b1 90.93<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Post hoc analysis was done using Wilcoxon\ntest to find out which measurement had different anti-S-RBD titers. Wilcoxon\ntest was done between pre vaccination and 21 days after first dose, pre\nvaccination and 56 days after second dose, and between 21 days after first dose\nand 56 days after second dose. The result was p<\/em> < 0.001 for all group\n(Table 3).<\/p>\n\n\n\n

Table 3: Post hoc analysis of anti-S-RBD IgG levels between all testing point<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Anti S-RBD <\/strong>IgG <\/strong>level (U\/mL)<\/strong><\/p>\n<\/td>\n

\n

n<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n

\n

Mean<\/strong><\/p>\n<\/td>\n

\n

p<\/em><\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Pre vaccine vs 21 days after 1st<\/sup> dose<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Pre vaccination<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

< 0.001<\/p>\n<\/td>\n<\/tr>\n

\n

21 days after 1st<\/sup> dose<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

2.7 (0-251)<\/p>\n<\/td>\n

\n

25.25 \u00b1 59.74<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Pre vaccine vs <\/strong>56<\/strong> days after <\/strong>2n<\/sup><\/strong>d<\/sup><\/strong> dose<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Pre vaccination<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

0<\/p>\n<\/td>\n

\n

< 0.001<\/p>\n<\/td>\n<\/tr>\n

\n

56 days after 2n<\/sup>d<\/sup> dose<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

128 (0-251)<\/p>\n<\/td>\n

\n

138.77 \u00b1 90.93<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

21 days after 1st<\/sup> dose vs <\/strong>56<\/strong> days after <\/strong>2n<\/sup><\/strong>d<\/sup><\/strong> dose<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

21 days after 1st<\/sup> dose<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

2.7 (0-251)<\/p>\n<\/td>\n

\n

25.25 \u00b1 59.74<\/p>\n<\/td>\n

\n

< 0.001<\/p>\n<\/td>\n<\/tr>\n

\n

56 days after 2n<\/sup>d<\/sup> dose<\/p>\n<\/td>\n

\n

172<\/p>\n<\/td>\n

\n

128 (0-251)<\/p>\n<\/td>\n

\n

138.77 \u00b1 90.93<\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

Our\nstudy provides the data of the S-RBD antibody titers measured on day 21 after\nfirst dose and 56 days after second dose of CoronaVac. The mean of the antibody\ntiters increased from 0 to 25.25 IU\/mL at 21 days after the administration of\nthe first dose and further increased to 138.77 IU\/mL 56 days after the second\ndose. The protective effect (based on >15 U\/mL cut-off), also followed with\nrapid seroconversion was observed as early as 21 days following the\nvaccination. Our previous study employing a smaller\nnumber of participants (n=60) suggests the mean antibody titers could reach a\nseroconversion rate of 91.6% with a mean value of 63.62\u00b182.57 IU\/mL.20<\/sup> Our findings are in line with a previously reported study\ninvestigating the Thai population, where mean value of S-RBD antibody titers of\n1.98 IU\/mL was obtained after the first dose of CoronaVac.21<\/sup> After\nthe second dose, the mean titer increased to 92.9 IU\/mL on day-30 and decreased\nto 49.4 IU\/mL on day-90, though the seroconversion rate persisted at 100%.21<\/sup> A\nstudy conducted in Banten of Indonesia also supported the immunogenicity of the\nCoronaVac vaccine after the second dose, where the median of the antibody\ntiters was 38.7 IU\/mL.22<\/sup> Inactivated virus vaccine has been suggested to be suitable for\nemergency use due to its rapid immunogenicity (14 days post-injection).15<\/sup> Regardless the immunogenicity, the protective level of CoronaVac\nvaccine against SARS-CoV-2 infectivity is low. In a published report\ninvestigating Indonesian health care workers, the recipients of two doses of\nCoronaVac were reported to remain at risk for SARS-CoV-2 infection.23<\/sup> <\/p>\n\n\n\n

In addition to\nthe immunogenicity, our findings suggest the safety of the CoronaVac with\n11.04% adverse reaction incidence after the first dose, and almost all\nvolunteers (171\/172) reported no side effects after the second dose. None of\nlife-threatening adverse reaction was observed after each shot, where most of\nthe participants felt feverish after the first dose. In previous reports, the\nmost common short-term side effects observed after the injection of either the\nfirst or the second dose of CoronaVac included fatigue, muscle pain, fever, and\nheadache.24,\n25<\/sup> The\nside effects frequency obtained in this present study is fewer as compared with\nthat obtained previously (35.6%) who employed a smaller number of seronegative\nparticipants (n=73).19<\/sup> Apart from the different number of participants, the gender ratio\nwas also different between this present study and the previous study19<\/sup>, which might play a role in the different adverse reaction\nfrequencies. In fact, several previous studies have witnessed that being female\nis associated with higher adverse reaction frequency, yet could induce higher\nimmunogenicity.26,\n27<\/sup> <\/p>\n\n\n\n

It is\nworth-mentioning that the waning efficacy of inactivated virus vaccine has been\nhighlighted by previous studies, in particular during the emergence of\nSARS-CoV-2 variants.28,\n29<\/sup>\nMoreover, a previous study also found the anti-S-RBD antibody titers were\nhigher in naturally infected individuals as compared with those vaccinated\nusing CoronaVac21<\/sup>.\nThird dose vaccination might be required to improve the protective effect of\nthe vaccine. A longitudinal study comparing the third immunization using\nCoronaVac and BNT162b2 vaccines suggests that heterogenous booster could induce\nhigher antibodies against SARS-CoV-2.30<\/sup> A study even reported the absence of inhibition effect of CoronaVac\nvaccine-induced antibodies against Omicron variant (strains HKU691 and\nHKU344-R346K).31<\/sup>\nHence, despite the rapid immunogenicity and low adverse reaction frequency,\nthird dose vaccination with mRNA-based vaccine might require for those who\nreceived two doses of CoronaVac.<\/p>\n\n\n\n

There are some\nlimitations of this study that need to discussed. We did not perform sera\ndilution for samples with concentration > 250 U\/mL, suggesting that the\nantibody titers could have higher concentration for those who had >250 U\/mL.\nThe number of male and female volunteers was not equal in our study of which\nmore dominated by male volunteers and this might cause bias. We did not\ninvestigate the change of antibody titers in the following months after the\nsecond dose, and therefore we are unable to monitor the length of the vaccine\nprotective time. Regardless the stated limitations, our study could describe\nthe rapid immunogenicity of CoronaVac vaccine following the first and second\ndose. Rapid immunogenicity is essential during the early time of pandemic,\nespecially in population that are at risk due to high intensity of\ninternational mobility such as Bali. <\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

CoronaVac could induce rapid seroconversion of at least 21 days following the first shot. Moreover, CoronaVac cause low adverse reactions, where none are life-threatening. Further studies are recommended with higher number of participants to assess the dynamic of specific anti-SARS-CoV-2 S-RBD antibody concentration following the second or even booster dose. <\/p>\n\n\n\n

Data sharing <\/strong><\/p>\n\n\n\n

The underlying dataset containing deidentified participants of this article is available from the corresponding author (SM) upon reasonable request and accompanied by IRB approval.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors do not have any conflict of interest. <\/p>\n\n\n\n

Funding Sources <\/strong><\/p>\n\n\n\n

 This study was funded by International Society of Travel Medicine to SM. Grant no. is 1330\/Unwar\/FKIK\/PD-13\/2022<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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