Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-vaccinated individuals in Indonesia

Harapan Harapan; Hibban Ar Royan; Islam Ing Tyas; Auda Nadira; Irham Faraby Abdi; Samsul Anwar; Milda Husnah; Ichsan Ichsan; Agung Pranata; Mudatsir Mudatsir; Maimun Syukri; Samsul Rizal; Razali .; Hamdani .; Rudi Kurniawan; Irwansyah Irwansyah; Sarwo Edhy Sofyan

doi:10.12688/f1000research.109676.1

Home Browse Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-vaccinated...

ALL Metrics

Views

Downloads

Get PDF

Get XML

Export

▬

✚

Research Article

Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-vaccinated individuals in Indonesia

[version 1; peer review: 1 approved with reservations, 1 not approved]

Harapan Harapan ^1-3, Hibban Ar Royan¹, Islam Ing Tyas¹, [...] Auda Nadira¹, Irham Faraby Abdi¹, Samsul Anwar⁴, Milda Husnah¹, Ichsan Ichsan^1-3,5, Agung Pranata⁶, Mudatsir Mudatsir^1-3, Maimun Syukri⁷, Samsul Rizal⁸, Razali .⁸, Hamdani .⁸, Rudi Kurniawan⁸, Irwansyah Irwansyah⁸, Sarwo Edhy Sofyan⁸

Harapan Harapan ^1-3, Hibban Ar Royan¹, [...] Islam Ing Tyas¹, Auda Nadira¹, Irham Faraby Abdi¹, Samsul Anwar⁴, Milda Husnah¹, Ichsan Ichsan^1-3,5, Agung Pranata⁶, Mudatsir Mudatsir^1-3, Maimun Syukri⁷, Samsul Rizal⁸, Razali .⁸, Hamdani .⁸, Rudi Kurniawan⁸, Irwansyah Irwansyah⁸, Sarwo Edhy Sofyan⁸

PUBLISHED 10 Mar 2022

Author details Author details

¹ Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia
² Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia
³ Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia
⁴ Department of Statistics, Faculty of Mathematics and Natural Sciences, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia
⁵ Tsunami and Disaster Mitigation Research Center (TDMRC), Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia
⁶ Department of Parasitology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia
⁷ Department of Internal Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia
⁸ Department of Mechanical and Industrial Engineering, Faculty of Engineering, Universitas Syiah Kuala, Banda Aceh, 23111, Indonesia

Harapan Harapan
Roles: Conceptualization, Methodology, Software, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Hibban Ar Royan
Roles: Data Curation, Investigation, Validation, Writing – Review & Editing

Islam Ing Tyas
Roles: Data Curation, Investigation, Validation, Writing – Review & Editing

Auda Nadira
Roles: Data Curation, Investigation, Validation, Writing – Review & Editing

Irham Faraby Abdi
Roles: Data Curation, Investigation, Validation, Writing – Review & Editing

Samsul Anwar
Roles: Formal Analysis, Validation, Writing – Review & Editing

Milda Husnah
Roles: Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Ichsan Ichsan
Roles: Supervision, Validation, Writing – Review & Editing

Agung Pranata
Roles: Resources, Validation, Writing – Review & Editing

Mudatsir Mudatsir
Roles: Resources, Supervision, Validation, Writing – Review & Editing

Maimun Syukri
Roles: Resources, Validation, Writing – Review & Editing

Samsul Rizal
Roles: Funding Acquisition, Resources, Validation, Writing – Review & Editing

Razali .
Roles: Funding Acquisition, Resources, Validation, Writing – Review & Editing

Hamdani .
Roles: Funding Acquisition, Resources, Validation, Writing – Review & Editing

Rudi Kurniawan
Roles: Funding Acquisition, Resources, Validation, Writing – Review & Editing

Irwansyah Irwansyah
Roles: Funding Acquisition, Resources, Validation, Writing – Review & Editing

Sarwo Edhy Sofyan
Roles: Funding Acquisition, Resources, Validation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Emerging Diseases and Outbreaks gateway.

This article is included in the Coronavirus collection.

Abstract

Background: The decrease of immunity acquired from COVID-19 vaccines is a potential cause of breakthrough infection. Understanding the dynamics of immune responses of vaccine-induced antibodies post-vaccination is important. This study aimed to measure the level of neutralizing antibody (NAb) anti-SRBD in individuals at different time points upon the receipt of the second dose of CoronaVac vaccine, as well as evaluate the plausible associated factors.
Methods: A cross-sectional study was conducted among CoronaVac-vaccinated residents in Banda Aceh, Indonesia. The level of NAb titre was measured using Elecsys Anti-SARS-CoV-2 S immunoassay. A set of standardized and validated questionnaires were used to assess the demographics and other plausible associated factors.
Results: Our results showed waning SARS-Cov-2 NAb titres over time post-vaccination. Compared to samples of the first month post-vaccination, the levels of NAb titres were significantly lower than those of five-months (mean 184.6 vs. 101.8 IU/mL, p = 0.009) and six-months post-vaccination (mean 184.6 vs. 95.59 IU/mL, p = 0.001). This suggests that the length of time post-vaccination was negatively correlated with antibody anti-SRBD titre. A protective level of NAbs titres (threshold of 15 IU/mL) was observed from all the samples vaccinated within one to three months; however, only 73.7% and 78.9% of the sera from five- and six-months possessed the protective titres against SARS-CoV-2, respectively. The titre of NAb anti-SRBD was found significantly higher in sera of individuals having a regular healthy meal intake compared to those who did not (mean 136.7 vs. 110.4 IU/mL, p = 0.044), including in subgroup analysis that included those five to six months post-vaccination only (mean 79.0 vs. 134.5 IU/mL, p = 0.009).
Conclusions: This study provides insights on the efficacy of CoronaVac vaccine in protecting individuals against SARS-CoV-2 infection over time, which may contribute to future vaccination policy management to improve and prolong protective strategy.

Keywords

COVID-19, neutralizing antibody, CoronaVac, anti-SRBD, Sinovac

Corresponding author: Harapan Harapan

Competing interests: No competing interests were disclosed.

Grant information: This research was funded by Lembaga Pengelola Dana Pendidikan (LPDP), managed by the Indonesian Science Fund (ISF) (Grant No: RISPRO/KI/B1/TKL/5/15448/2020). The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2022 Harapan H et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Harapan H, Ar Royan H, Tyas II et al. Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-vaccinated individuals in Indonesia [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2022, 11:300 (https://doi.org/10.12688/f1000research.109676.1) First published: 10 Mar 2022, 11:300 (https://doi.org/10.12688/f1000research.109676.1) Latest published: 12 Apr 2023, 11:300 (https://doi.org/10.12688/f1000research.109676.2)

Introduction

Prevention of severe coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated mortality is still a major hurdle worldwide. The disease is associated with several long-term consequences.¹^,² To date, no truly effective antivirals or therapeutic strategy has been successfully developed for the treatment of critical COVID-19. Some drugs, such as remdesivir and hydroxychloroquine, showed limited efficacy.³^,⁴ The presence of individual protective immunity, instead, could provide effective protection against acute SARS-CoV-2 infection.⁵ Therefore, understanding and profiling antibody response towards SARS-CoV-2 is highly prominent as it will provide significant insight into therapeutic approaches. Specific antibodies detection, as an indirect method for COVID-19 diagnosis, allows the evaluation of seroprevalence, promoting a better understanding of the COVID-19 transmission among communities. It also enables the identification of individuals potentially invulnerable to SARS-CoV-2 infection, monitoring of herd immunity, as well as formulating strategies for global COVID-19 vaccination.⁶^–⁸

Neutralizing antibodies (NAbs) provide real protective immunity as they play a crucial role in hampering the binding of the SARS-CoV-2 receptor-binding domain (RBD) of surface spike (S) protein to the human angiotensin-converting enzyme 2 (ACE2) receptor,⁹^–¹² blocking viral infection and minimizing disease severity. Therefore, measuring SARS-CoV-2 NAbs is considered an acceptable approach for the analysis of protective immune response against COVID-19 after vaccination.¹³

Vaccination triggers the neutralizing immune response, making vaccination an effective strategy to control virus-associated diseases although the acceptance rate varies among countries.¹⁴^,¹⁵ Vaccination programs for COVID-19 using various vaccine types have therefore been vigorously conducted, including the inactivated CoronaVac.¹⁶ Preclinical studies revealed the ability of CoronaVac to induce NAb production as well as providing partial and complete protection in the tested animals against COVID-19.¹⁷ This vaccine has also been reportedly well tolerated and induced the humoral immune responses in individuals aged 18–59 years.¹⁸ However, given the fact that reinfection still occurred in individuals vaccinated with CoronaVac and the vaccine-induced NAb titres have been reportedly waning over time, it is questionable to what extent this vaccine can persist and protect against SARS-CoV-2. Therefore, evaluating NAb response in individuals within a different duration of time upon CoronaVac vaccination is critically important, as it may serve as a predictor of vaccine protection efficacy. This study sought to evaluate the titre of anti-SARS-CoV-2 NAbs among CoronaVac-vaccinated individuals as well as to determine the potential factors associated with the level of the titre.

Methods

Study design and setting

A cross-sectional study among COVID-19-vaccinated residents in Banda Aceh, Indonesia was conducted from May to July 2021. The subjects were post COVID-19-vaccinated individuals residing in Banda Aceh who met the inclusion criteria. Individuals vaccinated with two doses of CoronaVac vaccine (Sinovac Biotech) within one to six months prior to the recruitment period, had never been diagnosed with COVID-19, and aged between 18 and 65 years were considered eligible for the study. Individuals who had COVID-19 after the vaccination or having symptoms during the period of recruitment and having malignant diseases were excluded. The recruitment was conducted based on COVID-19 vaccination records obtained from Prince Nayef Hospital Universitas, Syiah Kuala, Banda Aceh, Indonesia.

Study variables

The response variable was the level of SARS-CoV-2 NAb titre after CoronaVac vaccination, measured using ELISA. Several plausible factors that might be associated with the NAb titre were measured and collected. This included demographic characteristics such as age and gender, body mass index (BMI), history of illness, history of immunization (BCG and influenza), adverse events following vaccination (allergy, fever, arthralgia, and acute paralysis), exercise routine, smoking status, comorbidities (hypertension, diabetes, hyperlipidaemia, chronic obstructive pulmonary disease (COPD), asthma, and gout), sleep quality, and level of stress. BMI was measured by measuring participant height and weight. A set of standardized and validated questionnaires were used: (a) the quality of sleep was assessed according to Pittsburgh Sleep Quality Index (PSQI)¹⁹; and (b) the level of stress was determined based on the Depression Anxiety Stress Scales 42 (DASS-42).²⁰

SARS-CoV-2 NAb assay

The venous blood was collected and centrifuged to separate the sera. The sera were stored at -80°C until used. Specific anti S-RBD NAb titre was measured through an electrochemiluminescence immunoassay (ECLIA) method using Elecsys^® Anti-SARS-CoV-2 S immunoassay following the manufacturer’s instruction (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). The assay was conducted using an automatic Roche cobas^® E411 immunoassay analyzer (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). The assay uses a recombinant protein representing the RBD of the S antigen in a double-antigen sandwich assay approach. In brief, 20 μL of sample incubated with SARS-CoV-2-Ag~biotin (a biotinylated SARS-CoV-2 S-RBD-specific recombinant antigen) and SARS-CoV-2 Ag~Ru (bpy) (SARS-CoV-2 S-RBD-specific recombinant antigen labeled with a ruthenium complex) instruction (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). The complex became bound to the solid phase after streptavidin-coated microparticles were added. The reaction mixture was aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. The chemiluminescent emission was then measured by a photomultiplier. The titres of the SARS-CoV-2 NAb were then classified as protective and non-protective using a cut-off 15 U/mL.²¹

Statistical analysis

Analysis of variance (Anova) and Student t-test were used to compare the titres of SARS-CoV-2 NAb between demographic groups as appropriate. Linear regression was employed to determine factors affecting the NAb titre. Pearson correlation was used to assess the correlation between day of post vaccination, age and BMI with the titres of NAb. The analyses were conducted using SPSS version 20 (IBM SPSS Inc., Chicago, IL, USA) (RRID:SCR_019096).

Ethical approval

This study was approved by the Health Research Ethics Committee of the Faculty of Medicine, Universitas Syiah Kuala - Zainoel Abidin Hospital (#198/EA/FK-RSUDZA/2021 and KEPPKN Registration #1171012P). All the participants were informed of the study procedures and provided written consent prior to participating in this study.

Results

The level of S-RBD NAb titres

We measured the level of SARS-CoV-2 NAb titre in individuals with different length of time post the second dose. The individual titres and the mean titres of SARS-CoV-2 NAb from each group are presented in Figure 1. The mean of titre of the one-month group was 184.5 IU/mL and the mean decreased to 101.8 IU/mL in samples collected from those five-month post-vaccination and to 95.5 IU/mL in the six-month group. All samples from one to three months post-vaccination had protective SARS-CoV-2 NAb titres (more than 15 IU/mL). However, only 78.9% of the samples from six-months post-vaccination had a protective level of NAb titres against SARS-CoV-2.

Figure 1. The individual titres and the mean titres of SARS-CoV-2 NAb of different times of post vaccination.

Factor associated with the level of SARS-CoV-2 NAb titres

We assessed the association of some plausible factors with the titre of SARS-CoV-2 NAb (Table 1). Our data suggested that healthy meal intake was associated with the NAb titres. The titre of NAb anti-SRBD was higher in those who took regular healthy meal compared to those who did not (136.7 vs. 110.4 IU/mL, p = 0.044) (Table 1). When we included only those who were vaccinated within five to six months (n = 76), only regular healthy meal intake was associated with the level of SARS-CoV-2 NAb anti-SRBD (79.0 vs 134.5 IU/mL) (Table 2).

Table 1. Linear regression showing the predictor neutralizing antibody anti-SRBD titre post-vaccination (n = 115).

Characteristic	n (%)	Mean concentration (±SD), IU/mL	Initial model		Final model
Characteristic	n (%)	Mean concentration (±SD), IU/mL	ß (95% CI)	p–value	ß (95% CI)	p–value
Post-vaccination time (month)
1 (Reference, R)	16 (13.9)	184.6 (±79.9)
2	10 (8.7)	180.1 (±81.9)	12.9 (-75.1, 100.9)	0.771	9.8 (-65.7, 85.3)	0.797
3	6 (5.2)	95.6 (±89.0)	-57.5 (-159.1, 44.0)	0.263	-99.8 (-188.6, -11.1)	0.028
4	7 (6.1)	127.0 (±103.5)	-49.9 (-146.1, 46.3)	0.305	-50.6 (-134.1, 32.9)	0.232
5	38 (33.0)	101.8 (±102.2)	-70.3 (-134.9, -5.7)	0.033	-74.3 (-129.5, -19.1)	0.009
6	38 (33.0)	95.6 (±95.2)	-96.2 (-155.8, -36.7)	0.002	-93.3 (-148.2, -38.4)	0.001
Age (year)
20-30 (R)	59 (51.3)	122.0 (±93.7)
31-40	32 (27.8)	127.3 (±109.5)	3.5 (-49.4, 56.3)	0.896
41-50	16 (13.9)	117.5 (±108.4)	-4.9 (-70.4, 60.7)	0.883
>50	8 (7.0)	71.0 (±80.6)	-6.5(-100.3, 87.4)	0.892
Gender
Male (R)	38 (33.0)	121.9 (±102.2)
Female	77 (67.0)	118.0 (±98.4)	-34.3 (-83.8, 15.2)	0.172
Body mass index (BMI)
Underweight (R)	11 (9.6)	102.0 (±99.1)
Normal	35 (30.4)	125.8 (±96.4)	13.9 (-57.1, 85.0)	0.698
Overweight	26 (22.6)	103.2 (±99.2)	12.3 (-64.2, 88.9)	0.750
Obesity	43 (37.4)	128.2 (±103.4)	24.5 (-47.3, 96.3)	0.500
Regular exercise
Yes	32 (27.8)	103.2 (±98.3)	2.2 (-47.7, 52.1)	0.930
No (R)	83 (72.2)	125.5 (±99.5)
Sleep quality
Good	40 (34.8)	98.1 (±95.1)	-45.5 (-87.6, -3.4)	0.035	-30.0 (-66.6, 6.6)	0.107
Poor (R)	75 (65.2)	130.6 (±100.2)
Healthy meal
No	76 (66.1)	110.4 (±98.8)	-46.7 (-93.4, 0.1)	0.050	-39.2 (-77.3, -1.0)	0.044
Yes (R)	39 (33.9)	136.7 (±99.2)
Regular food supplementation
Yes	65 (56.5)	116.6 (±98.5)	15.3 (-25.2, 55.8)	0.454
No (R)	50 (43.5)	122.8(±101.1)
Smoking
Yes (R)	10 (8.7)	100.1 (±107.1)
No	105 (91.3)	121.1 (±98.9)	20.4 (-63.4, 104.2)	0.630
Stress level
Normal (R)	96 (83.5)	123.2 (±101.5)
Mild	5 (4.3)	76.1 (±97.8)	-81.6 (-182.2, 18.9)	0.110
Moderate	7 (6.1)	88.6 (±74.0)	-66.8 (-153.7, 20.2)	0.131
Severe	7 (6.1)	126.8 (±96.4)	1.75 (-77.0, 80.5)	0.965
Stress
Yes	19 (16.5)	99.4 (±86.8)	NA (NA, NA)	NA
No (R)	96 (83.5)	123.2 (±101.5)
Comorbidity
Hypertension
Yes (R)	6 (5.2)	45.1 (±46.3)
No	109 (94.8)	123.4 (±99.9)	65.5 (-25.3, 156.3)	0.155
Hyperlipidaemia
Yes (R)	8 (7.0)	53.0 (±80.4)
No	107 (93.0)	124.2 (±99.1)	44.6 (-42.1, 131.3)	0.309
Gout
Yes (R)	13 (11.3)	103.9 (±94.1)
No	102 (88.7)	121.2 (±100.2)	35.1 (-39.6, 109.7)	0.353
History of infection except COVID-19
Yes (R)	15 (13.0)	135.9 (±94.7)	18.4 (-43.5, 80.3)	0.556
No	100 (87.0)	116.8 (±100.2)
Experience of vaccination side effect
No (R)	58 (50.4)	118.2 (±98.8)
Yes	57 (49.6)	120.4 (±100.7)	4.9 (-36.7, 46.5)	0.815
History of flu vaccination
Yes	24 (20.9)	107.1 (±96.0)	-13.9 (-63.2, 35.4)	0.577
No (R)	91 (79.1)	122.5 (±100.4)

Table 2. Linear regression showing the predictor neutralizing antibody anti-SRBD titre 5-6 months post-vaccination (n = 76).

Characteristic	n (%)	Mean concentration (±SD), IU/ml	Initial model		Final model
Characteristic	n (%)	Mean concentration (±SD), IU/ml	ß (95% CI)	p–value	ß (95% CI)	p–value
Post-vaccination time (month)
5 (R)	38 (50.0)	101.8 (±102.2)
6	38 (50.0)	95.6 (±95.2)	-30.2 (-86.8, 26.3)	0.289
Age (year)
20-30 (R)	34 (44.7)	103.6 (±93.6)
31-40	26 (34.2)	114.4 (±111.8)	-6.6 (-71.1, 57.9)	0.838
41-50	11 (14.5)	72.0 (±91.7)	-69.9 (-158.3, 18.5)	0.119
>50	5 (6.6)	42.7 (±39.3)	-14.9 (-178.1, 148.2)	0.855
Gender
Male (R)	25 (32.9)	100.9 (±102.3)
Female	51 (67.1)	97.6 (±97.1)	-3.0 (-68.6, 62.6)	0.928
Body mass index (BMI)
Underweight (R)	8 (10.5)	85.4 (±102.8)
Normal	18 (23.7)	86.2 (±87.1)	24.2 (-65.0, 113.4)	0.588
Overweight	21 (27.6)	92.7 (±97.8)	47.0 (-49.8, 143.7)	0.334
Obesity	29 (38.2)	114.5 (±106.3)	33.6 (-56.6, 123.7)	0.459
Regular exercise
Yes	24 (31.6)	92.4 (±98.4)	19.2 (-45.4, 83.8)	0.553
No (R)	52 (68.4)	101.6 (±98.9)
Sleep quality
Good	27 (35.5)	82.4 (±95.6)	-40.0 (-96.2, 16.1)	0.159
Poor (R)	49 (64.5)	107.7 (±99.4)
Healthy meal
No	49 (64.5)	79.0 (±89.6)	-78.1 (-142.6, -13.7)	0.018	-62.3 (-108.5, -16.1)	0.009
Yes (R)	27 (35.5)	134.5 (±104.5)
Regular food supplementation
Yes	48 (63.2)	94.4 (±95.4)	23.0 (-32.2, 78.2)	0.407
No (R)	28 (36.8)	106.1 (±104.1)
Smoking
Yes (R)	6 (7.9)	91.7 (±123.2)
No	70 (92.1)	99.3 (±96.8)	-14.8 (-122.8, 93.3)	0.785
Stress level
Normal (R)	66 (86.8)	104.2 (±103.0)
Mild	3 (3.9)	34.4 (±13.8)	-162.5 (-296.7, -28.2)	0.019	-90.6 (-203.3, 22.2)	0.114
Moderate	3 (3.9)	76.9 (±19.2)	-37.3 (-166.9, 92.2)	0.566	-48.0 (-160.7, 64.7)	0.399
Severe	4 (5.3)	73.2 (±65.5)	-27.5 (-139.9, 84.9)	0.626	-25.8 (-123.3, 71.7)	0.599
Stress
Yes	10 (132)	62.7 (±44.0)	NA (NA, NA)	NA
No (R)	66 (86.8)	104.2 (±103.0)
Comorbidity
Hypertension
Yes (R)	5 (6.6)	45.2 (±51.7)
No	71 (93.4)	102.5 (±99.8)	66.9 (-49.8, 183.6)	0.255
Hyperlipidaemia
Yes (R)	6 (7.9)	23.1 (±24.9)
No	70 (92.1)	105.2 (±99.4)	55.5 (-78.2, 189.1)	0.409
Gout
Yes (R)	6 (7.9)	73.9 (±94.7)
No	70 (92.1)	100.8 (±98.8)	11.4 (-109.3, 132.1)	0.851
History of infection except COVID-19
Yes (R)	7 (9.2)	91.7 (±85.1)	-3.2 (-93.0, 86.6)	0.943
No	69 (90.8)	99.4 (±99.9)
Experience of vaccination side effect
No (R)	39 (51.3)	94.3 (±94.1)
Yes	37 (48.7)	103.4 (±103.4)	4.9 (-53.4, 63.2)	0.867
History of flu vaccination
Yes	15 (19.7)	65.5 (±69.5)	-53.0 (-117.9, 11.9)	0.108
No (R)	61 (80.3)	106.9 (±102.8)

Our data suggest that the length of post-vaccination time was associated with the NAb titres after adjustment (Table 1). Compared to those in first month of vaccination, the level of NAb titres were significantly lower from individuals five months-post vaccination (184.6 vs. 101.8 IU/mL, p = 0.009). Similarly, the level of NAb titres was significantly lower in samples from individuals six-months post vaccination (184.6 vs. 95.59 IU/mL, p = 0.001) (Table 1). Spearman’s rank correlation (r_s) also showed that the time of post vaccination was correlated negatively with antibody anti-SRBD titre (Table 3). This indicated that the longer time post-vaccination the lower NAb anti-SRBD titre.

Table 3. Spearman’s rank correlation (r_s) showing predictor of neutralizing antibody anti-SRBD titre post-vaccination (n = 115).

Correlation of variables	r_s (95%CI)	p-value
Time of post vaccination (day) - antibody anti-SRBD titre	-0.273 (-0.437, -0.091)	0.003
Age - antibody anti-SRBD titre	-0.135 (-0.311, 0.050)	0.150
BMI - antibody anti-SRBD titre	-0.030 (-0.212, 0.154)	0.750

Discussion

Our results revealed waning neutralizing immunity in individuals after vaccination with CoronaVac vaccine. We noted a significant decline in the level of SARS-CoV-2 NAb titre five and six months after the receipt of the second dose of the vaccine when compared to the first month (Figure 1 and Table 1), suggesting that the time of post vaccination was negatively correlated with antibody anti-SRBD titre. Reduction in vaccine-induced neutralization titres within the first six months upon the second dose vaccination has also been previously reported in several different vaccines.²²^–²⁵ However, a similar study suggested that the decrease in CoronaVac-induced anti-S antibodies levels was faster in individuals without prior SARS-CoV-2 infection compared to those with previous infection.²⁶ NAbs can persist in the body for two to 12 months after the infection onset.⁵^,²⁷ This might suggest that CoronaVac would assumingly provide greater and longer-lasting protective impact when administered in previously infected individuals, as it may boost the memory immune cells that developed following the infection.²⁷^,²⁸

The underlying causes of rapid waning of vaccine induced NAbs remains to be determined. However, several studies reported that waning NAb titres have been associated with IgG anti-RBD immune response²⁹^,³⁰ and neutralizing capacity was positively correlated with IgG antibody titres.³¹ Furthermore, the loss of short-lived plasma cells has been considered the cause of initial rapid waning of antibodies in SARS-CoV-2 infected individuals in general, while establishment of long-lived plasma was thought to contribute to the elevation of antibody level.³²^,³³ Defective Bcl6+ follicular T-cells due to the absence of germinal centers in the thoracic lymph nodes in dead COVID-19 patients was proposedly unable to activate memory B-cells, leading to a decrease in long-lasting and high-affinity antibody production.³⁴ This mechanism has been suggested as a potential explanation regarding rapid antibody decline in SARS-CoV-2.³⁴

This study suggested that more than 20% of the sample of five- and six-month post-vaccination had NAb titres <15 IU/mL compared to those of one to three months, suggesting a loss of protection after three months of vaccination against SARS-CoV-2 (Table 2). Reduction in the level of protective antibody might be due to the decreased NAb titres as waning antibody titres have been reportedly correlated with reduced protection over time.¹²^,²⁵^,³⁵ This remarkable reduction in the titre of SARS-CoV-2 NAb anti-SRBD and its decline in protective level might indicate the need for an additional booster dose of CoronaVac vaccine to protect against COVID-19 among individuals without prior SARS-CoV-2 infection.

Our findings suggested the level of SARS-CoV-2 NAb anti-SRBD was significantly associated with a regular intake of healthy meals, regardless of the duration post-vaccination (Tables 1 and 2). An adequate intake of vitamins such as vitamin A, B12, B6, and C, zinc, as well as iron is suggested to maintain immune function, particularly during COVID-19.³⁶ Vitamin C has been known to boost the immune system and prevent any viral infection.³⁶^,³⁷ Healthy meals and optimal nutritional intake will impact the immune system through cell activation, signalling molecule modification, and gene expression. A variety of dietary components also determines the composition of gut microbes which then form the immune response in the body.³⁸

Conclusions

We assessed the level of anti-SARS-CoV-2 neutralizing antibody titre in CoronaVac-vaccinated individuals. Our data indicated that the level of NAb titres dropped significantly within five and six months after the second dose of CoronaVac vaccination, along with the decay of protective capacity in several samples. Our study suggested that the length of time post-vaccination negatively correlated with the level of NAb titres. Regular healthy meal intake was associated significantly with the level of NAb, regardless of the duration post-vaccination. This provided a prediction of CoronaVac vaccine efficacy in protecting individuals against SARS-CoV-2 infection over time upon the second dose vaccination. This may contribute to future vaccination policy management to improve and prolong the protective strategy through vaccination.

Data availability

Underlying data

Figshare: Underlying data for ‘Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-vaccinated individuals in Indonesia’. https://doi.org/10.6084/m9.figshare.19149797.³⁹

This project contains the following underlying data:

- Data file: Master Data.xlsx [Table containing the raw data of the study]

Reporting guidelines

Figshare: STROBE checklist for ‘Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-vaccinated individuals in Indonesia'. https://doi.org/10.6084/m9.figshare.19149806.⁴⁰

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgements

The authors would like to thank to staff at Dr. Imai Indra Laboratory, Prince Nayef Hospital Universitas Syiah Kuala, and Prodia Laboratory Banda Aceh, Indonesia, for assistance during the study. We would like to thank Narra Studio Jurnal Indonesia for its assistance during the manuscript preparation.

References

1. Fajar JK, Ilmawan M, Mamada S, et al.: Global prevalence of persistent neuromuscular symptoms and the possible pathomechanisms in COVID-19 recovered individuals: A systematic review and meta-analysis. Narra. J. 2021; 1(3). Publisher Full Text
2. Fahriani M, Ilmawan M, Fajar JK, et al.: Persistence of long COVID symptoms in COVID-19 survivors worldwide and its potential pathogenesis-a systematic review and meta-analysis. Narra. J. 2021; 1(2). Publisher Full Text
3. Musa A, Pendi K, Hashemi A, et al.: Remdesivir for the Treatment of COVID-19: A Systematic Review of the Literature. West. J. Emerg. Med. 2020; 21(4): 737–741. PubMed Abstract | Publisher Full Text
4. Sarma P, Kaur H, Kumar H, et al.: Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: a systematic review and meta-analysis. J. Med. Virol. 2020; 92(7): 776–785. PubMed Abstract | Publisher Full Text
5. Dispinseri S, Secchi M, Pirillo MF, et al.: Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival. Nat. Commun. 2021; 12(1): 1–12.
6. Sethuraman N, Jeremiah SS, Ryo A: Interpreting diagnostic tests for SARS-CoV-2. JAMA. 2020; 323(22): 2249–2251. Publisher Full Text
7. Abbasi J: The promise and peril of antibody testing for COVID-19. JAMA. 2020; 323(19): 1881–1883. PubMed Abstract | Publisher Full Text
8. Bohn MK, Loh TP, Wang C-B, et al.: IFCC interim guidelines on serological testing of antibodies against SARS-CoV-2. Clinical Chemistry and Laboratory Medicine (CCLM). 2020; 58(12): 2001–2008. PubMed Abstract | Publisher Full Text
9. Du L, He Y, Zhou Y, et al.: The spike protein of SARS-CoV—a target for vaccine and therapeutic development. Nat. Rev. Microbiol. 2009; 7(3): 226–236. PubMed Abstract | Publisher Full Text
10. Iwasaki A, Yang Y: The potential danger of suboptimal antibody responses in COVID-19. Nat. Rev. Immunol. 2020; 20(6): 339–341. PubMed Abstract | Publisher Full Text
11. Shang J, Wan Y, Luo C, et al.: Cell entry mechanisms of SARS-CoV-2. Proc. Natl. Acad. Sci. 2020; 117(21): 11727–11734. PubMed Abstract | Publisher Full Text
12. Premkumar L, Segovia-Chumbez B, Jadi R, et al.: The receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci. Immunol. 2020; 5(48): eabc8413. PubMed Abstract | Publisher Full Text
13. Padoan A, Bonfante F, Pagliari M, et al.: Analytical and clinical performances of five immunoassays for the detection of SARS-CoV-2 antibodies in comparison with neutralization activity. EBioMedicine. 2020; 62: 103101. PubMed Abstract | Publisher Full Text
14. Rosiello DF, Ferreto LED, Aburto JTO, et al.: Acceptance of COVID-19 vaccination at different hypothetical efficacy and safety levels in ten countries in Asia, Africa, and South America. Narra. J. 2021; 1(3). Publisher Full Text
15. Hassan W, Kazmi SK, Tahir MJ, et al.: Global acceptance and hesitancy of COVID-19 vaccination: A narrative review. Narra. J. 2021; 1(3). Publisher Full Text
16. Creech CB, Walker SC, Samuels RJ: SARS-CoV-2 vaccines. JAMA. 2021; 325(13): 1318–1320. Publisher Full Text
17. Gao Q, Bao L, Mao H, et al.: Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020; 369(6499): 77–81. PubMed Abstract | Publisher Full Text
18. Zhang Y, Zeng G, Pan H, et al.: Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect. Dis. 2021; 21(2): 181–192. PubMed Abstract | Publisher Full Text
19. Buysse DJ, Reynolds CF III, Monk TH, et al.: The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989; 28(2): 193–213. PubMed Abstract | Publisher Full Text
20. Crawford JR, Henry JD: The Depression Anxiety Stress Scales (DASS): Normative data and latent structure in a large non-clinical sample. Br. J. Clin. Psychol. 2003; 42(2): 111–131. Publisher Full Text
21. Tekol SD, Altıntaş MM, Yılmaz E, et al.: Detection and Evaluation of Antibodies to SARS CoV-2 Spike Protein in Healthcare Workers After Inactivated COVID-19 (CoronaVac) Vaccination. South. Clin. Istanb. Eurasia. 2021; 32(3). Publisher Full Text
22. Levin EG, Lustig Y, Cohen C, et al.: Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months. N. Engl. J. Med. 2021; 385: e84. PubMed Abstract | Publisher Full Text
23. Pegu A, O’Connell SE, Schmidt SD, et al.: Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants. Science. 2021; 373(6561): 1372–1377. PubMed Abstract | Publisher Full Text
24. Falsey AR, Frenck RW Jr, Walsh EE, et al.: SARS-CoV-2 neutralization with BNT162b2 vaccine dose 3. N. Engl. J. Med. 2021; 385(17): 1627–1629. PubMed Abstract | Publisher Full Text
25. Khoury DS, Cromer D, Reynaldi A, et al.: Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 2021; 27: 1205–1211. Publisher Full Text
26. Cucunawangsih C, Wijaya RS, Lugito NPH, et al.: Antibody response to the inactivated SARS-CoV-2 vaccine among healthcare workers, Indonesia. Int. J. Infect. Dis. 2021; 113: 15–17. PubMed Abstract | Publisher Full Text
27. Muena NA, García-Salum T, Pardo-Roa C, et al.: Long-lasting neutralizing antibody responses in SARS-CoV-2 seropositive individuals are robustly boosted by immunization with the CoronaVac and BNT162b2 vaccines. medRxiv. 2021.
28. Abbasi J: Study suggests lasting immunity after covid-19, with a big boost from vaccination. JAMA. 2021; 326(5): 376–377. PubMed Abstract | Publisher Full Text
29. Bruni M, Cecatiello V, Diaz-Basabe A, et al.: Persistence of anti-SARS-CoV-2 antibodies in non-hospitalized COVID-19 convalescent health care workers. J. Clin. Med. 2020; 9(10): 3188. PubMed Abstract | Publisher Full Text
30. Billon-Denis E, Ferrier-Rembert A, Garnier A, et al.: Differential serological and neutralizing antibody dynamics after an infection by a single SARS-CoV-2 strain. Infection. 2021; 1–3.
31. Yalçın TY, Topçu Dİ, Doğan Ö, et al.: Immunogenicity after two doses of inactivated virus vaccine in healthcare workers with and without previous COVID-19 infection: Prospective observational study. J. Med. Virol. 2021; 94(1): 279–286.
32. McAndrews KM, Dowlatshahi DP, Dai J, et al.: Heterogeneous antibodies against SARS-CoV-2 spike receptor binding domain and nucleocapsid with implications for COVID-19 immunity. JCI insight. 2020; 5(18). PubMed Abstract | Publisher Full Text
33. Smith KG, Hewitson TD, Nossal G, et al.: The phenotype and fate of the antibody-forming cells of the splenic foci. Eur. J. Immunol. 1996; 26(2): 444–448. PubMed Abstract | Publisher Full Text
34. Ren L, Fan G, Wu W, et al.: Antibody Responses and Clinical Outcomes in Adults Hospitalized With Severe Coronavirus Disease 2019 (COVID-19): A Post hoc Analysis of LOTUS China Trial. Clin. Infect. Dis. 2021; 72(10): e545–e551. PubMed Abstract | Publisher Full Text
35. Thomas SJ, Moreira ED Jr, Kitchin N, et al.: Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months. N. Engl. J. Med. 2021; 385(19): 1761–1773. PubMed Abstract | Publisher Full Text
36. Aman F, Masood S: How Nutrition can help to fight against COVID-19 Pandemic. Pakistan Journal of Medical Sciences. 2020; 36(COVID19-S4): S121–S123. PubMed Abstract | Publisher Full Text
37. Haug A, Brand-Miller JC, Christophersen OA, et al.: A food “lifeboat”: food and nutrition considerations in the event of a pandemic or other catastrophe. Med. J. Aust. 2007; 187(11/12): 674–676. Publisher Full Text
38. Aslam MF, Majeed S, Aslam S, et al.: Vitamins: Key role players in boosting up immune response—A mini review. Vitam Miner. 2017; 6(1): 1318–2376.
39. Harapan H: Master Data of Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-Vvccinated individuals in Indonesia. figshare. Journal Contribution. 2022.
40. Harapan H: STROBE checklist for Waning anti-SARS-CoV-2 neutralizing antibody in CoronaVac-vaccinated individuals in Indonesia. figshare. Journal Contribution. 2022.

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 10 Mar 2022