超高齢者は新型コロナウイルスmRNAワクチンの四回接種により変異株BQ.1.1およびXBBにも有効な交差性中和抗体を獲得する

概要

Kobe University Repository : Kernel
PDF issue: 2024-05-02

Fourth mRNA vaccination increases crossneutralizing antibody titers against SARS-CoV-2
variants, including BQ.1.1 and XBB, in a very
elderly population

SILVIA, SUTANDHIO
(Degree)
博士（医学）

(Date of Degree)
2023-09-25

(Resource Type)
doctoral thesis

(Report Number)
甲第8733号

(URL)
https://hdl.handle.net/20.500.14094/0100485917
※ 当コンテンツは神戸大学の学術成果です。無断複製・不正使用等を禁じます。著作権法で認められている範囲内で、適切にご利用ください。

（課程博士関係）

学 位 論 文 の 内 容 要 旨

Fourth mRNA vaccination increases
cross-neutralizing antibody titers against
SARS-CoV-2 variants, including BQ.1.1 and XBB,
in a very elderly population

超高齢者は新型コロナウイルス mRNA ワクチンの四回接種により
変異株 BQ.1.1 および XBB にも有効な交差性中和抗体を獲得する

神戸大学大学院医学研究科医科学専攻
臨床ウイルス学
（指導教員：森

康子

教授）

Silvia Sutandhio

シルヴィア スタンディオ

1. Introduction
Infection by Severe Acute Respiratory Syndrome - Coronavirus 2 (SARS-CoV2) can cause Coronavirus Disease 2019 (COVID-19). COVID-19 has been a
pandemic that had caused over 6.7 million deaths worldwide. Vaccination is the most
reliable measure to prevent infection and to reduce the morbidity and mortality of
COVID-19. Since Omicron variants with immune evasion ability had emerged, they
have mutated rapidly and raised concerns about the weakening of vaccine efficacy,
and the very elderly populations are vulnerable to severe COVID-19. To assess
whether 3rd and 4th vaccinations can induce neutralizing antibodies against the newly
appeared variants for the elderly, we analyzed the cross-neutralizing antibodies for
several SARS-CoV-2 variants (D614G, Delta, Omicron BA.2, BA.5, BA.2.75,
BQ.1.1, and XBB) after 3rd and 4th mRNA vaccinations in a very elderly population.
2. Materials and Methods
Blood samples were taken from elderly residents at four long-term care facilities
in Hyogo prefecture, Japan (Koyukai Nishi Hospital, Subaru Uozaki-no-sato, Subaru
Rokko, and Carehome Subaru) (median age, 91 years). Participants were divided into
two groups based on the total number of vaccination doses they had received, namely
three (n=67) or four (n=48). Underlying medical conditions of participants were also
documented. The mRNA vaccines administered were Comirnaty (BNT162b2, PfizerBioNTech) for the 1st to 3rd doses, and either Comirnaty or Spikevax (mRNA-1273,
Moderna) for the 4th vaccination. Blood samples were taken at two time points, i.e.,
103 days after 3rd vaccination and 48 days after 4th vaccination. A live virus
microneutralization assay was performed. Two-fold serial dilution of serum samples
were done to determine neutralizing antibody titers against SARS-CoV-2 variants.
The enzyme-linked immunosorbent assay (ELISA) method was done to detect
anti-SARS-CoV-2-Spike (S) of conventional (D614G) virus, Omicron BA.2, BA.5,
and BA.2.75 variants or -Nucleocapsid (N) immunoglobulin G (IgG) antibodies in
participants’ sera. Samples from participants who had a history of COVID-19
infection (confirmed by polymerase-chain reaction) or high serum titers of anti-N
antibody were analyzed separately from the main group.
3. Results
Neutralizing antibody titers increased after 4th vaccination
After the 4th vaccination, the neutralizing antibody titers increased significantly
compared to 3rd vaccination: 2.6-fold, 2.0-fold, 4.2-fold, 3.5-fold, 2.7-fold, 1.9-fold,

and 2.0-fold, for D614G, Delta, Omicron BA. 2, BA.5, BA.2.75, BQ.1.1, and XBB,
respectively. The neutralizing antibodies potency decreased with each emerging
variant. Although the neutralizing antibody positivity rate increased with 4 doses of
vaccine, the titers of those against BQ.1.1 and XBB was still low.
We compared neutralizing antibody titers of participants aged under 90 years old
and 90 years or more. Neutralizing antibody positivity rates and titers were similar
between the participants aged less than- and over 90 years, at both time points.
Participants’ medical conditions were disclosed during the recruitment process;
these included hypertension, hyperlipidemia, diabetes mellitus, chronic heart disease,
chronic respiratory disease, cerebrovascular disease, and malignancy. There was no
significant difference found in neutralizing antibody titers after the 3rd or 4th
vaccination among the various medical conditions.
Anti-SARS-CoV-2-S antibody titers were correlated with neutralizing antibody titers
By ELISA, anti-S IgG was detected in all participants’ samples. The binding
affinity of anti-S IgG was significantly increased for the SARS-CoV-2 S protein of
the D614G, Omicron BA.2, BA.5, and BA.2.75 variants, respectively, after the 4th
vaccination. We found a moderate-to-strong positive correlation of anti-S titers and
neutralizing antibody titers, with correlation coefficients (r) of 0.55, 0.77, 0.73, and
0.74 for D614G, BA.2, BA.5, and BA.2.75, respectively.
Reactivity to N protein alone was not enough to screen for past infection
During participant recruitment, we excluded some participants from the 3rd
vaccination (n=5) and 4th vaccination (n=6) groups based on their COVID-19 history
and sera reactivity towards the N protein. An excluded participant who was infected
in April 2021 (before the emergence of Delta variant) had a high titer of anti-N IgG
at both time points, i.e., after the 3rd and 4th vaccinations. But two other excluded
participants who were infected after the emergence of Delta and Omicron variants,
i.e., in 2022, displayed low titer of anti-N (below cut-off value).
Excluded participants had higher positivity rates of cross-neutralizing antibodies
Excluded participants (3rd vaccination group, n=5; 4th vaccination group, n=6),
i.e., who have either history of COVID-19 or high reactivity to N protein had higher
positivity rates and titers of cross-neutralizing antibodies against SARS-CoV-2
variants. However, even after 4th vaccination, cross-neutralizing antibody titers
against BQ.1.1 and XBB were lower than that against the other variants.

4. Discussion
Since the Comirnaty and Spikevax mRNA vaccines used for 3rd and 4th
vaccination were made based on wild type SARS-CoV-2 S, the numerous mutations
in Omicron variants result in immune escape. Omicron BQ.1.1 is a descendant of
BA.5, while XBB is a mixture product of BA.2.10.1 and BA.2.75. Specifically, the
Spike proteins of BQ.1.1 and XBB have the same R346T, N460K, and F486X
mutations, with additional K444T mutation in BQ.1.1 and V445P, G446S, and F490S
mutations in XBB, which conferred resistance to many monoclonal antibodies. Our
result showed that after 3rd vaccination, the positivity rates and titers of neutralizing
antibody against D614G and Delta variant were higher than those against Omicron
variants. Adequate neutralizing antibodies for Omicron BA.2 were induced after 3rd
vaccination. Those for BA.5 and BA.2.75 were also induced, albeit at lower levels
than BA.2. After 4th vaccination, positivity rates and titers of neutralizing antibody
against all tested variants, including BQ.1.1 and XBB, were increased, indicating that
the 4th vaccination is important for the elderly. The cross-neutralizing antibody
positivity rates and titers induced by 4th vaccination in the elderly population aged
under 90 years old were similar to those aged 90 years old or more. Neutralizing assay
results of the excluded participants’ sera showed higher positivity rates of crossneutralizing antibody against all tested variants compared to naïve vaccinated
individuals, indicating the immune booster effects by previous infection, although
cross-neutralizing antibody titers against BQ.1.1 and XBB were still low.
Antibodies against the N protein may be elicited after infection with SARS-CoV2, but not after COVID-19 mRNA vaccination. The discrepancy of N protein titers
between previously and recently infected individuals may need further investigation.
Had we not used past COVID-19 history as another exclusion criteria, we would have
incorrectly grouped some of the participants who had hybrid immunity (i.e., immunity
conferred by past infection and vaccinations). We reported that the use of N proteinbased serology tests to determine history of infection may not be accurate in elderly
populations who have received multiple vaccinations.
We reported that the 4th mRNA vaccination can readily induce crossneutralizing antibodies against many SARS-CoV-2 variants in the very elderly
population. However, it may not be enough to protect them from newer variants, e.g.,
BQ.1.1 and XBB. Considering the rapid mutation of viruses and the efficacy of
vaccines, it may be necessary to create a system that can develop vaccines suitable
for each epidemic in consideration of the epidemic of the virus.

神戸大学大学院医学（
系）
研究科（博士課程）
言合互文亡苓皆三審ミクつ糸吉長艮 クつ塁廷旨示

3322

氏

名

甲第

号

受付番号

SILVIASUTANDHIO

超高齢者は新型コロナウイルス mRNA ワクチ ンの四 回接種により

.
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