Magnitude and Duration of Serum Neutralizing Antibody Titers Induced by a Third mRNA COVID-19 Vaccination against Omicron BA.1 in Older Individuals

Jun-Sun Park; Jaehyun Jeon; Jihye Um; Youn Young Choi; Min-Kyung Kim; Kyung-Shin Lee; Ho Kyung Sung; Hee-Chang Jang; BumSik Chin; Choon Kwan Kim; Myung-don Oh; Chang-Seop Lee

doi:10.3947/ic.2023.0057

. 2023 Nov 1;56(1):25–36. doi: 10.3947/ic.2023.0057

Magnitude and Duration of Serum Neutralizing Antibody Titers Induced by a Third mRNA COVID-19 Vaccination against Omicron BA.1 in Older Individuals

Jun-Sun Park ¹, Jaehyun Jeon ^2,^*, Jihye Um ¹, Youn Young Choi ³, Min-Kyung Kim ², Kyung-Shin Lee ¹, Ho Kyung Sung ¹, Hee-Chang Jang ⁴, BumSik Chin ², Choon Kwan Kim ⁵, Myung-don Oh ⁶, Chang-Seop Lee ^7,^8,^*

PMCID: PMC10990888 PMID: 38014726

Abstract

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) is dominating coronavirus disease 2019 (COVID-19) worldwide. The waning protective effect of available vaccines against the Omicron variant is a critical public health issue. This study aimed to assess the impact of the third COVID-19 vaccination on immunity against the SARS-CoV-2 Omicron BA.1 strain in older individuals.

Materials and Methods

Adults aged ≥60 years who had completed two doses of the homologous COVID-19 vaccine with either BNT162b2 (Pfizer/BioNTech, New York, NY, USA, BNT) or ChAdOx1 nCoV (SK bioscience, Andong-si, Gyeongsangbuk-do, Korea, ChAd) were registered to receive the third vaccination. Participants chose either BNT or mRNA-1273 (Moderna, Norwood, MA, USA, m1273) mRNA vaccine for the third dose and were categorized into four groups: ChAd/ChAd/BNT, ChAd/ChAd/m1273, BNT/BNT/BNT, and BNT/BNT/m1273. Four serum specimens were obtained from each participant at 0, 4, 12, and 24 weeks after the third dose (V1, V2, V3, and V4, respectively). Serum-neutralizing antibody (NAb) activity against BetaCoV/Korea/KCDC03/2020 (NCCP43326, ancestral strain) and B.1.1.529 (NCCP43411, Omicron BA.1 variant) was measured using plaque reduction neutralization tests. A 50% neutralizing dilution (ND₅₀) >10 was considered indicative of protective NAb titers.

Results

In total, 186 participants were enrolled between November 24, 2021, and June 30, 2022. The respective groups received the third dose at a median (interquartile range [IQR]) of 132 (125 - 191), 123 (122 - 126), 186 (166 - 193), and 182 (175 - 198) days after the second dose. Overall, ND₅₀ was lower at V1 against Omicron BA.1 than against the ancestral strain. NAb titers against the ancestral strain and Omicron BA.1 variant at V2 were increased at least 30-fold (median [IQR], 1235.35 [1021.45 - 2374.65)] and 129.8 [65.3 - 250.7], respectively). ND₅₀ titers against the ancestral strain and Omicron variant did not differ significantly among the four groups (P = 0.57). NAb titers were significantly lower against the Omicron variant than against the ancestral strain at V3 (median [IQR], 36.4 (17.55 - 75.09) vs. 325.9 [276.07 - 686.97]; P = 0.012). NAb titers against Omicron at V4 were 16 times lower than that at V3. Most sera exhibited a protective level (ND₅₀ >10) at V4 (75.0% [24/32], 73.0% [27/37], 73.3% [22/30], and 70.6% [12/17] in the ChAd/ChAd/BNT, ChAd/ChAd/m1273, BNT/BNT/BNT, and BNT/BNT/m1273 groups, respectively), with no significant differences among groups (P = 0.99).

Conclusion

A third COVID-19 mRNA vaccine dose restored waning NAb titers against Omicron BA.1. Our findings support a third-dose vaccination program to prevent the waning of humoral immunity to SARS-CoV-2.

Keywords: COVID-19 vaccine third dose; Humoral immunity; Antibodies, Neutralizing; SARS-CoV-2 Omicron variant

Graphical Abstract

INTRODUCTION

Shortly after the first case of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (BA.1 sub-lineage of B 1.1.529) had been confirmed in South Africa on November 21, 2021, the World Health Organization documented that this variant had spread worldwide [1]. The Omicron variant replaced the Delta variant as the dominant strain in many countries, and substantial mutations in its spike protein reduced vaccine effectiveness [2,3,4].

Advanced age is the most critical risk factor for coronavirus disease 2019 (COVID-19)-related morbidity and mortality [5]. Therefore, vaccination against COVID-19 has been strongly recommended in many countries to prevent severe COVID-19 in older individuals, thereby reducing the incidence of COVID-19 and its associated mortality [6]. However, despite the high primary (first two doses) vaccination rate in Korea, the incidence of COVID-19 among older people has unexpectedly been higher than among other age groups. In the third week of November 2021, the incidence of COVID-19 was 52.1 cases per 100,000 people among those aged 60 years or more, which was approximately 1.4 times higher than that of the overall population (37.5 cases per 100,000 people), while 57.5% of the critical cases occurred due to breakthrough infections, according to a report by the Korea Disease Control and Prevention Agency [7].

Accordingly, the Korean government rolled out the third dose (i.e., booster dose) of the COVID-19 vaccine [8]. The BNT162b2 (Pfizer/BioNTech, New York, NY, USA) and mRNA-1273 (Moderna, Norwood, MA, USA) vaccines have been deemed the official third COVID-19 vaccines in Korea. Healthcare workers and residents of long-term care facilities received the third dose with the highest priority, followed by older individuals (age >65 years), and the rate of the third dose of COVID-19 vaccination among the older population had reached 90% as of November 7, 2022 [9]. The high rate of administering the third dose, as well as a combination of interventions such as social distancing, masking, testing, isolation, and contact tracing, have mitigated the spread of SARS-CoV-2, the development of severe COVID-19, and its related morbidity and mortality [10].

Despite the effectiveness of the third COVID-19 vaccination against the ancestral and Delta variants, studies have reported lower effectiveness of the mRNA booster vaccine against Omicron relative to that observed against other SARS-CoV-2 variants [11,12,13,14,15]. Additionally, the appropriate timing of booster vaccination and the duration of its effect in older individuals have not yet been fully elucidated.

A better understanding of the immunological characteristics upon vaccination, such as the magnitude and duration of vaccine-induced immunity, is valuable in the decision-making process for COVID-19 immunization programs. Moreover, a lower neutralizing antibody titer is associated with more breakthrough infections and higher risks of symptomatic COVID-19 [10]. Therefore, we evaluated neutralizing antibody (NAb) response against Omicron BA1.1.529 before and after the third dose of monovalent mRNA vaccination, and the duration of protective NAb titers after the third vaccination in Korea.

MATERIALS AND METHODS

1. Study population

We conducted a prospective cohort study to examine SARS-CoV-2 spike NAb responses following a third dose of COVID-19 mRNA vaccination with BNT162b2 or mRNA-1273. Between November 24, 2021, and June 30, 2022, individuals aged ≥60 years without any immunocompromised condition or previous SARS-CoV-2 infection were enrolled in this study. All participants had received two homologous doses of the ChAdOx1 nCoV (SK bioscience, Andong-si, Gyeongsangbuk-do, Korea, ChAd/ChAd group) or BNT162b2 (BNT/BNT group) vaccines, according to the national vaccination campaign. Participants voluntarily enrolled to receive the BNT162b2 or mRNA-1273 vaccine as the third dose. Participants that had received a second dose ≥120 days before the third dose were eligible for the third dose of the COVID-19 vaccine. Age, sex, height, body weight, and underlying diseases were recorded as the demographic characteristics of the participants. Solicited local (e.g., erythema, pain, and swelling) and systemic adverse effect (e.g., fever, chill, fatigue, headache, muscle aches, joint pain, and diarrhea) data were collected on the third and seventh day after vaccination by phone call and upon every visit by self-reporting on a scale of 0 to 4 (0 for no symptoms; 1 for asymptomatic or mild symptoms, intervention not indicated; 2 for moderate symptoms, minimal, local, or noninvasive intervention indicated; 3 for severe but not immediately life-threatening symptoms, hospitalization indicated, 4 for life-threatening consequences, urgent intervention indicated; 5 for death related to adverse events). Blood samples for analysis of NAb titers against SARS-CoV-2 were collected at four-time points: on the day of the third vaccination (V1) and 4 (V2), 12 (V3), and 24 weeks (V4) after the third dose (Supplementary Fig. 1). The participants were categorized into four groups: ChAd/ChAd/BNT, ChAd/ChAd/m1273, BNT/BNT/BNT, and BNT/BNT/m1273 for analysis and follow-up. Participants who self-reported a COVID-19 diagnosis during the follow-up period or whose enzyme-linked immunosorbent assay (ELISA) results were positive for anti-SARS-CoV-2-NC-IgG were excluded from the analysis.

2. Ethics statement

Written informed consent was obtained from each participant. The institutional review board of the National Medical Center granted ethical and regulatory approval (IRB No. NMC-2021-03-027). This study was performed in accordance with the Declaration of Helsinki and its later amendments.

3. Immunologic assessment

A plaque reduction neutralization test (PRNT) was used to measure the 50% neutralizing dilution (ND₅₀) for quantification of NAb titers against the ancestral SARS-CoV-2 strain (BetaCoV/Korea/KCDC03/2020, NCCP43326) and the Omicron BA.1 (B.1.1.529, NCCP43411) variant, respectively. Heat-inactivated (56°C, 30 min) serum samples were serially diluted two-fold from a ratio of 1: 2 to 1: 16,384 with Dulbecco’s modified Eagle’s medium containing 2% fetal bovine serum and 1% penicillin/streptomycin. All diluted samples were pre-incubated with 50 plaque-forming units of SARS-CoV-2 viruses in cell-free plates for 1 h at 37°C for a neutralization reaction.

After the neutralization reaction, the virus-serum solutions were inoculated to 2 × 10⁵ VeroE6 cells/mL (KCTC, AC28803, Jeongup, Korea) using a 12-well plate. The plates were incubated at 37°C in 5% CO₂ for 1 h, and the inocula were removed. Then, the plates were overlaid with 1 mL of minimum essential medium containing 0.75% agarose and 2% fetal bovine serum and incubated again under the same conditions for 3 - 5 days. After incubation, the cells were fixed in 7% formaldehyde solution and stained with crystal violet. Infected cells in the plates were stained with 0.07% crystal violet, 10% formaldehyde, and 5% ethanol for counting. The ND₅₀ was calculated using the Karber formula: log₁₀ ND₅₀ = m-Δ (∑p-0.5), and tests were performed twice independently for each sample [16].

4. Anti-SARS-CoV-2 nucleocapsid antibody assay

To avoid confounding influence by a robust humoral immune response to the mRNA vaccine after previous natural infection in older individuals, which has been reported in previous studies [17], the anti-SARS-CoV-2 nucleocapsid (NC) antibody titer was evaluated. NC protein, which is an immunodominant antigen of natural virus, is not present in the vaccine, and an antibody against NC protein can be used as a surrogate marker of past exposure [18]. An anti-SARS-CoV-2 NC antibody test was conducted on all samples using ELISA with an EDI™ COVID-19 Nucleocapsid IgG Quantitative ELISA Kit (KT-1034; Epitope Diagnostics, Inc. San Diego, CA, USA) [19]. The ELISA kit provided a microplate-based enzyme immunoassay using microtiter wells in a microplate coated with COVID-19 recombinant full-length NC protein and a horseradish peroxidase-labeled polyclonal goat anti-human IgG tracer antibody, which were used to create a COVID-19 recombinant antigen–human anti-COVID-19 IgG antibody–horseradish peroxidase-labeled anti-human IgG tracer antibody immunocomplex. The immunocomplex titer was measured using a spectrophotometric microplate reader (Spectramax M4, Molecular Devices, San Jose, CA, USA). According to the manufacturer's instructions, an IgG titer of 6.78 U/mL was the cut-off value of positivity reflecting SARS-CoV-2 infection.

5. Statistical analysis

Descriptive data are presented as the median ± interquartile range (IQR). The counted NAb titers were changed into geometric mean titers for comparison. SPSS version 29 (IBM SPSS Statistics, Inc.,Armonk, NY, USA) was used to compare NAb titers among groups. The t, Kruskal–Wallis, and Mann–Whitney U tests were used to compare continuous data of independent groups, and the paired sample chi-square and Wilcoxon signed-rank tests were used for categorical data. A two-tailed P-value <0.05 was considered statistically significant.

RESULTS

1. Demographic characteristics

Between November 24, 2021, and June 30, 2022, 186 individuals participated in this study.

The median age of the participants was 69.5 (interquartile range: 65 - 78) years. The proportion of males and females was 40.3 and 59.7%, respectively. Fifty-three participants with the primary series of ChAd/ChAd received BNT and were categorized into the ChAd/ChAd/BNT group. Accordingly, 62 participants were categorized into the ChAd/ChAd/m1273, 51 into the BNT/BNT/BNT, and 21 into the BNT/BNT/m1273 group (Fig. 1). The demographic characteristics of each group are provided in Table 1. The overall median interval between the second dose and V1 was 155.8 (147 - 177) days. The ChAd/ChAd/BNT, ChAd/ChAd/m1273, BNT/BNT/BNT, and BNT/BNT/m1273 groups received the third dose a median of 132 (125 - 191), 123 (122 - 126), 186 (166 - 193), and 182 (175 - 198) days after the second dose, respectively. We did not assess the NAb titers against the ancestral strain in the BNT/BNT/m1273 group at any time point or in the BNT/BNT/BNT group at V3 or V4 in consideration of the limited laboratory capacity under the Omicron variant-related COVID-19 surge in Korea.

This study was conducted prospectively between November 24, 2021, and June 30, 2022. Seropositivity for exclusion was determined by antibody seroconversion using ELISA at each visit. Seroconversion was defined as a serum anti-nucleocapsid antibody titer over 0.67 U/mL.

BNT, BNT162b2 vaccine (Pfizer); ChAd, ChAdOx1 nCoV-19 vaccine (AstraZeneca); M1273, mRNA-1273 vaccine (Moderna); V1, the day of 3rd vaccination; V2, 1 month from V1; V3, 3 months from V1; V4, 6 months from V1.

Table 1. Demographic characteristics of study participants by vaccine type.

Characteristics		ChAd/ChAd		BNT/BNT		P-value
Characteristics		BNT (n = 53)	m1273 (n = 62)	BNT (n = 51)	m1273 (n = 21)	P-value
Age, median, years		64 (62 - 65)	68 (65 - 71)	79 (78 - 83)	79 (76 - 81)	<0.0001
Sex, female, n (%)		33 (62.2)	33 (53.2)	31 (62.0)	14 (66.6)	0.6241
BMI, median, kg/m²		24.7 (23.0 - 25.9)	25.8 (24.1 - 28.4)	23.7 (22.4 - 26.4)	25.0 (22.9 - 26.2)	0.0039
Time intervals, days
	2nd dose to V1	132 (125 - 191)	123 (122 - 126)	186 (166 - 193)	182 (175 - 198)	<0.0001^a
	V2	24 (23 - 25)	25 (23 - 27)	25 (24 - 27)	26 (26 - 28)	0.0002^a
	V3	78 (72 - 80)	72 (70 - 77)	83 (76 - 84)	85 (76 - 86)	<0.0001^a
	V4	155 (154 - 168)	156 (154 - 160)	157 (154 - 160)	158 (155 - 163)	0.7600^a
Anti-SARS-CoV-2 NC Ab positive sero-conversion^b, n (%)
	Total	19 (35.8)	22 (35.5)	10 (20.0)	3 (14.3)	0.084
	V1 - V2	7 (13.2)	5 (8.1)	1 (2.0)	3 (14.3)	0.166
	V2 - V3	7 (13.2)	4 (6.5)	1 (2.0)	1 (4.8)	0.154
	V3 - V4	16 (30.2)	16 (25.8)	9 (18.0)	2 (9.5)	0.198
Underlying diseases, n (%)
	Hypertension	13 (24.5)	38 (61.2)	28 (56.0)	11 (52.3)	0.0006
	Diabetes mellitus	5 (9.4)	17 (27.4)	13 (26.0)	6 (28.5)	0.0744
	Cancer	4 (7.5)	0 (0)	1 (2.0)	0 (0)	0.0793^c
	COPD	1 (1.9)	1 (1.1)	1 (2.0)	1 (4.7)	0.7243^c

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Data are presented as the median (IQR) or frequency (%) as appropriate.

^aKruskal–Wallis test.

^bAntibody seroconversion was defined as a serum anti-nucleocapsid antibody concentration over 0.67 U/mL.

^cFisher’s exact test.

ChAd, ChAdOx1 nCoV-19 vaccine (SK bioscience, Andog-si, Gyeongsangbuk-do, Korea); BNT, BNT162b2 vaccine (Pfizer, New York, NY, USA); m1273, mRNA-1273 vaccine (Moderna, Norwood, MA, USA); BMI, body mass index; V1, the day of 3rd vaccination; V2, 4 weeks from V1; V3, 12 weeks from V1; V4, 24 weeks from V1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; NC, nucleocapsid; Ab, antibody; COPD, chronic obstructive pulmonary disease; IQR, interquartile range.

In the solicited adverse events report, 51.8% of the participants experienced mild local symptoms within 7 days after the third vaccination, and 47.1% experienced mild systemic side effects. No difference was observed in the rate of adverse events by the kind of the third vaccine (BNT and m1273; Supplementary Table 1).

We analyzed serum samples from a total of 186 participants (n = 53, 62, 50, and 21 in the ChAd/ChAd/BNT, ChAd/ChAd//m1273, BNT/BNT/BNT, and BNT/BNT/m1273 groups, respectively) to determine the neutralization titers (Fig. 1).

A total of 55 participants were seropositive for the anti-SARS-CoV-2-NC antibody, indicating a natural SARS-CoV-2 infection (16, 8, and 31 participants at V1, V2, and V3, respectively; Fig. 1). The rate of natural infection was similar between the groups (Table 1).

The median value of the NAb titers before positive seroconversion of the anti-SARS-CoV-2-NC antibody was not significantly lower than the value of the anti-SARS-CoV-2-NC antibody negative groups against the ancestral strain (36.5 [18.7 - 100.3] vs. 36.7 [18.3 - 68.0] [P = 0.86] at V1, 1235.7 [1140.5 - 2208.9] vs. 1235.4 [934.3 - 2391.5] [P = 0.89] at V2, and 42.6 [27.7 - 138.8] vs. 37.0 [18.2 - 76.4] [P = 0.77] at V3) and Omicron BA.1 variant (5.7 [5.6 - 9.6] vs. 5.6 [5.6 - 5.7] [P = 0.09], 146.1 [79.8 - 154.4] vs. 124.5 [64.3 - 249.6] [P = 0.99] at V2, and 395.6 [264.4 - 1059.5] vs. 327.2 [276.5 - 641.2] [P = 0.26] at V3).

2. Neutralizing antibody titers

A significantly higher proportion of serum samples at V1 showed a protective level (ND₅₀ > 10) against the ancestral strain (89.8% [114/127]) than to Omicron BA.1 (6.4% [12/187], P < 0.001). However, the proportion of the serum samples above the protective ND₅₀ level against the ancestral strain was not significantly higher than that against Omicron BA.1 (100% [112/112] vs. 98.2% [164/167], P = 0.277; Fig. 2). Although the NAb titer against Omicron BA.1 gradually decreased over time, 73.3% (85/116) of the serum samples remained above the protective ND₅₀ level at V4 (Fig. 3A).

Serum samples obtained from participants who received mRNA-1273 or BNT162b2 as the third vaccine dose (booster) were assessed. Neutralization of ancestral SARS-CoV-2 and Omicron BA.1 was measured using the plaque reduction neutralization test. ^*Serum samples were collected from participants shortly before administration of the third dose on day 1 (V1) and at least 4 (V2), 12 (V3), and 24 (V4) weeks after the third dose. The P-value of the difference in neutralizing antibody titers between groups (the top of the box plot) and median titers (the solid line in each box plot) as well as the median titer values are presented. The horizontal gray dashed lines among the x-axes indicate the cut-off value (1:10). The 50% neutralizing dilution (ND50) antibody titer was calculated using the Karber formula. The lower limit of detection of the assay was 5.7. Values below the lower limit of detection were assigned a value of 5.6 (ns: not significant). The statistical significance of the differences between variants and individual groups are shown (P >0.05, ns).

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Serum samples were collected from participants shortly before administration of the third dose on day 1 (V1) and at 4 (V2), 12 (V3), and 24 (V4) weeks after the third dose.

The NAb titer against ancestral SARS-CoV-2 was not assessed. The P-value of the difference in neutralizing antibody titers between groups (the top of the box plot) and median titers (the solid line in each box plot) as well as the median titer values are presented. The horizontal gray dashed lines among the x-axes indicate the cut-off value (1 : 10). The lower limit of detection of the assay was 5.7. Values below the lower limit of detection were assigned a value of 5.6 (ns: not significant). The statistical significance of the differences between variants and individual groups are shown (P >0.05, ns).

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

The median NAb titers (IQR, n) against the ancestral strain were 36.7 (18.4 - 71.6, 127), 1235.3 (1021.5 - 2374.7, 112), and 325.9 (276.1 - 686.9) at V1, V2, and V3, respectively. The median NAb titers (IQR, n) against the Omicron BA.1 variant were 5.6 (5.6 - 5.7, 187), 129.8 (65.3 - 250.7, 167), 37.5 (19.25 - 77.0, 149), and 21.2 (10.4 - 147.4, 116) at V1, V2, V3, and V4, respectively (Fig. 3A). Therefore, the NAb titers against the ancestral strain at V1, V2, and V3 were significantly higher than those against Omicron BA.1 (P <0.001; Supplementary Table 2), 6.6-, 9.5-, and 8.7-fold, respectively.

Moreover, the NAb titers against the ancestral strain and Omicron BA.1 increased 33.7-fold and 23.2-fold between V1 and V2, respectively, and decreased 0.26-fold and 0.28-fold between V2 and V3. Additionally, the NAb titers against Omicron BA.1 decreased 0.56-fold between V3 and V4. The fold-change in the NAb titers was larger for the ancestral strain than for the Omicron BA.1 variant from V1 to V3 (P <0.001; Fig. 3A). However, the overall fold-change of the NAb titers was larger for Omicron BA.1 than for the ancestral strain (P <0.001). Among participants who received the first two vaccines with ChAd (ChAd/ChAd) or BNT (BNT/BNT), the anti-SARS-CoV-2 NAb titers at V2 were significantly higher in the BNT/BNT group than in the ChAd/ChAd group (Supplementary Table 2, Fig. 3B). However, the NAb titers against the ancestral strain and Omicron BA.1 were not significantly different. In an analysis of NAb titers by the third vaccine type, no difference was observed between the NAb titers of participants who received the BNT162b2 vaccination and those who received the mRNA-1273 vaccination (Supplementary Table 3). Finally, the ND₅₀ of the ChAd/ChAd/BNT, ChAd/ChAd/m1273, BNT/BNT/BNT, and BNT/BNT/m1273 groups at each follow-up day did not differ significantly among the groups (Table 2, Fig. 3C).

Table 2. Plaque reduction neutralization titer by vaccination group.

Visit	Viral strain	ChAd/ChAd/BNT	ChAd/ChAd/m1273	BNT/BNT/BNT	BNT/BNT/m1273	P-value^a
V1	Ancestral strain	37.0 (17.65 - 66.08)	36.6 (18.7 - 70.73)	48.5 (26.65 - 127.37)	-^b	0.753
	Ancestral strain	53	62	13	0	0.753
	Omicron BA.1	5.7 (3.35 - 8.34)	5.7 (4.13 - 5.98)	<5.7^c	<5.7^c	0.293
	Omicron BA.1	53	62	50	21	0.293
V2	Ancestral strain	1,144.34 (990.97 - 2,134.38)	1,256.5 (647.3 - 2,348.3)	4,121.92 (3,633.89 - 9,233.74)	-^c	<0.001^d
	Ancestral strain	46	57	9	0	<0.001^d
	Omicron BA.1	122.01 (68.12 - 240.7)	135.6 (63.74 - 263.71)	121.9 (63.3 - 256.0)	140.7 (68.13 - 383.85)	0.930
	Omicron BA.1	46	57	47	17	0.930
V3	Ancestral strain	320.84 (281.09 - 608.24)	508.32 (255.66 - 1,082.31)	-^b	-^b	0.550
	Ancestral strain	42	54	-^b	-^b	0.550
	Omicron BA.1	35.93 (19.15 - 64.48)	36.25 (17.12 - 75.52)	36.4 (16.9 - 84.64)	37.8 (13.96 - 312.09)	0.643
	Omicron BA.1	42	54	44	17	0.643
V4	Omicron BA.1	18.95 (9.65 - 80.11)	18.6 (9.8 - 47.09)	35.1 (9.8 - 314.61)	18.9 (9.65 - 209.27)	0.614
V4	Omicron BA.1	32	37	30	17	0.614

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Data are presented as the median (IQR) or number (n) as appropriate.

^aKruskal–Wallis test.

^bThe NAb titer against ancestral SARS-CoV-2 was not assessed as it has been replaced with variants of SARS-CoV-2 in Korea.

^cThe detection threshold was defined as neutralizing antibody (NAb) titers 5.7.

^dThe NAb titers of BNT/BNT/BNT were higher than those of the others.

ChAd, ChAdOx1 nCoV-19 vaccine (SK bioscience, Andog-si, Gyeongsangbuk-do, Korea); BNT, BNT162b2 vaccine (Pfizer, New York, NY, USA); m1273, mRNA-1273 vaccine (Moderna, Norwood, MA, USA); V1, the day of 3rd vaccination; V2, 4 weeks from V1; V3, 12 weeks from V1; V4, 24 weeks from V1; IQR, interquartile range; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

DISCUSSION

Herein, we report changes in NAb titers after the third dose of mRNA COVID-19 vaccines, BNT1622 and mRNA-1273, and their longevity against the wild-type and Omicron variants of SARS-CoV-2 in older individuals.

Our data indicate the impact of the Omicron variant on humoral immunity induced by the standard (two-dose) vaccination regimen. Our findings demonstrate that neutralization ability fell below the detection threshold 16 to 24 weeks after the first two doses of COVID-19 vaccines (at V1) against Omicron BA.1, with either the BNT162b2 or ChOxAd vaccine, while the titer against the wild-type was well maintained. The absence of neutralization ability to the Omicron variant at V1 implies that the protection against infection is reduced faster, as mentioned in a previous study [20]. The spike protein mutations of the Omicron variant may contribute to the low level of NAb titers [21,22,23,24]. Hoffmann et al. reported that the second dose of BNT162b2 inhibited entry of the Omicron spike (Pango lineages B.1.1.529, BA.1, BA.2, and BA.3) with 34-fold and 12-fold lower efficiency compared to the B.1. and Delta spikes, respectively [25]. The limited neutralizing activity against the Omicron variant after the primary COVID-19 vaccine likely leads to breakthrough infections in individuals who underwent the primary vaccine series [26]. Furthermore, Andrews et al. suggested that protection against infection and mild symptomatic disease 15 weeks after the second dose of BNT162b2 could be <50% for the Omicron variant, compared with 63.5% for the Delta variant [27].

We also showed that the third dose of mRNA vaccination restored Omicron-specific neutralization 28 days after vaccination, although the NAb titer was lower than that against the wild-type variant. The third dose of the mRNA COVID-19 vaccine has been reported to elicit a higher PRNT titer against the Omicron variant [28]. Although a correlation between higher antibody titers and higher vaccine efficacy has been reported in several studies, the clinical efficacy and protection of high NAb titers against Omicron remain unknown [20,29]. If the protective threshold of the convalescent NAb titer (PRNT₅₀ >160), provided by the US Food and Drug Administration, is used, at least a PRNT₅₀ level of 32 may be needed for 50% protection [30,31]. If we apply these approximate threshold estimations against wild-type SARS-CoV-2 to our data, 21.9 - 40.6%, 16.2 - 40.5%, 36.7 - 53.3%, and 29.4 - 35.3% of the participants in the ChAd/ChAd/BNT, ChAd/ChAd/m1273, BNT/BNT/BNT, and BNT/BNT/m1273 groups, respectively, can be considered to have 50% protective NAb titers against the Omicron variant, 24 weeks after the third vaccination. Our results are consistent with other similar studies [32]. However, the protective threshold of NAb against SARS-CoV-2 is variable according to disease severity, age, and race [33]. Thus, a greater understanding of the relationship between measured immunity and clinical protection against Omicron infection is needed for booster-dose planning and more efficient vaccine development [21,23,24].

In our data, the third vaccination significantly increased NAb titers in every group without significant differences among the groups. This result shows that the NAb response generated by the third vaccine may effectively restore immunity against both wild-type and Omicron SARS-CoV-2 [34,35]. Gruwell et al. reported a more than a 100-fold increase in neutralizing serum activity following the third dose of BNT162b2 against Omicron (27% of individuals that received the primary vaccine displayed detectable serum neutralizing activity) [28].

Our data demonstrated lower NAb titers against Omicron relative to those against the wild-type strain, even after the third mRNA vaccination. This result underscores the ability of the Omicron variant to escape from neutralization by the third dose of the COVID-19 mRNA vaccine. The overall median NAb titer against Omicron was 8.9- and 9.5-fold lower than that against wild-type SARS-CoV-2 at V2 and V3, respectively. The effectiveness of vaccines against the Omicron variant may be significantly less than that against wild-type SARS-CoV-2 because of the mutations distributed in the major target region of the NAb [4]. Accumulating data consistently suggest that NAb titers against the Omicron variant are lower than those against other variants of SARS-CoV-2 [28,36]. For example, Hoffmann et al. reported that serum from individuals who received three doses of BNT126b2 inhibited the entry of the B.1 and Delta spikes eight and two times more efficiently in comparison with the Omicron spike, respectively [25].

The median NAb titer value against the Omicron variant was reduced 6.7-fold within 24 weeks after the third vaccination. Although NAb titers by the third dose waned over 24 weeks, the neutralizing effect against the Omicron variant was maintained above the detectable threshold in more than 70% of vaccinees after the third dose at V4, even though the NAb titer of every participant at V1 was below the detection level. In the analysis of NAb against the wild-type strain, the titers were not below the detection threshold in all the groups. This result suggests that a third dose may provide a longer duration of NAb response than two doses, thereby supporting the need for booster doses. Our results are consistent with other contemporary studies of similar design [32].

Age is the most crucial factor affecting the magnitude and duration of NAb responses after COVID-19 mRNA vaccination [37]. However, differences in restored immunity by three or more doses of the SARS-CoV-2 vaccine according to age are not well understood, especially regarding the Omicron variant. Nevertheless, repetitive vaccination is thought to diminish the negative impact of advanced age on humoral responses and provide cross-protection against the Omicron variant [38,39].

Our current study has several limitations. First, our study population was only representative of the healthy older population, which may limit the generalizability of the results. Immunocompromised individuals or those residing in long-term care facilities were also excluded. Second, differences in the time between the second and the third vaccinations were inevitable due to the national immunization campaign recommendations. Third, the NAb titers of the BNT/BNT groups at V1 may have been underestimated due to the longer interval between the second and the third vaccinations than those in the ChAd/ChAd groups. Fourth, the participants were not randomly assigned to the different regimen groups, which could have resulted in bias due to dissimilarities between each group. Finally, our data provided only partial information on the potential side effects of the vaccines due to the small study population. However, none of the participants experienced severe adverse effects, and all reported mild adverse reactions. Despite these limitations, our work suggests that NAb activity increases after the booster BNT162b2 and mRNA-1273 vaccines, which could induce robust neutralization to overcome the immune evasion of the Omicron variant.

In conclusion, our data revealed that the neutralizing activity against SARS-CoV-2, including the wild-type and Omicron variants, waned rapidly 12–16 weeks after the first two doses of BNT162b2 or ChAdOX1. The third dose of BNT162b2 or mRNA-1273 could restore the NAb titers in the elderly. Additionally, we found that the NAb titers against the wild-type and Omicron variants after the third mRNA vaccination were more durable than the titers after the second dose.

ACKNOWLEDGMENTS

We would like to thank the staff of the Clinical Infectious Disease Research Center at the National Medical Center, Korea. We would like to thank Editage (www.editage.co.kr) for English language editing.

Footnotes

Funding: This work was supported by the National Institute of Infectious Diseases, National Institute of Health, and Korea Disease Control and Prevention Agency (grant No. 2021ER230400).

Conflicts of Interest: No conflict of interest.

Author Contributions:

Conceptualization: MDO, JSP, JJ.
Data curation: KSL, HKS.
Software: KSL.
Formal analysis: JJ.
Funding acquisition: HCJ.
Investigation: YYC, MKK, CKK, CSL.
Methodology: JU, JSP, JJ, MDO.
Validation: JJ, MDO.
Visualization: KSL.
Writing - original draft: JJ.
Writing - review & editing: JSP, YYC, BSC, CKK, CSL, MDO.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Solicited adverse events within 7 days after the third vaccine

ic-56-25-s001.xls^{(30KB, xls)}

Supplementary Table 2

Plaque reduction neutralization titer (PRNT) by primary vaccine type

ic-56-25-s002.xls^{(30.5KB, xls)}

Supplementary Table 3

Plaque reduction neutralization titer (PRNT) by third vaccine type

ic-56-25-s003.xls^{(30KB, xls)}

Supplementary Figure 1

Schedule for participant vaccination, testing, and follow-up. This study involved a prospective cohort of adults aged ≥ 60 years who had received two homologous doses of the BNT162b2 or ChAdOx vaccine and underwent at least one serologic assay after receipt of the third vaccine dose (V1) with the BNT162b2 or the mRNA-1273 vaccine. Samples were collected from the participants at 1 (V2), 3 (V3), and 6 (V4) months after receipt of the third dose. * 8 weeks for BNT162b2, 12 weeks for ChAdOx, ≥ 12 weeks between the 2nd and 3rd dose; the 1st and 2nd vaccinations administered were homologous vaccines (BNT162b2 or ChAdOx1); 3rd: the third vaccination was either BNT162b2 or mRNA-1273. Abbreviations: V1, day of the 3rd vaccination; V2, 1 month from V1; V3, 3 months from V1; V4, 6 months from V1.

ic-56-25-s004.ppt^{(338.5KB, ppt)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1

Solicited adverse events within 7 days after the third vaccine

ic-56-25-s001.xls^{(30KB, xls)}

Supplementary Table 2

Plaque reduction neutralization titer (PRNT) by primary vaccine type

ic-56-25-s002.xls^{(30.5KB, xls)}

Supplementary Table 3

Plaque reduction neutralization titer (PRNT) by third vaccine type

ic-56-25-s003.xls^{(30KB, xls)}

Supplementary Figure 1

ic-56-25-s004.ppt^{(338.5KB, ppt)}

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PERMALINK

Magnitude and Duration of Serum Neutralizing Antibody Titers Induced by a Third mRNA COVID-19 Vaccination against Omicron BA.1 in Older Individuals

Jun-Sun Park

Jaehyun Jeon

Jihye Um

Youn Young Choi

Min-Kyung Kim

Kyung-Shin Lee

Ho Kyung Sung

Hee-Chang Jang

BumSik Chin

Choon Kwan Kim

Myung-don Oh

Chang-Seop Lee

Abstract

Background

Materials and Methods

Results

Conclusion

Graphical Abstract

INTRODUCTION

MATERIALS AND METHODS

1. Study population

2. Ethics statement

3. Immunologic assessment

4. Anti-SARS-CoV-2 nucleocapsid antibody assay

5. Statistical analysis

RESULTS

1. Demographic characteristics

Figure 1. Flowchart of the study process.

Table 1. Demographic characteristics of study participants by vaccine type.

2. Neutralizing antibody titers

Figure 2. Neutralizing antibody responses against ancestral SARS-CoV-2 and the Omicron variant before the third mRNA vaccination.

Figure 3. Duration of neutralizing antibody responses against ancestral SARS-CoV-2 and the Omicron variant.

Table 2. Plaque reduction neutralization titer by vaccination group.

DISCUSSION

ACKNOWLEDGMENTS

Footnotes

SUPPLEMENTARY MATERIALS

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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