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COVID-19 vaccination with BNT162b2 and ChAdOx1 vaccines has the potential to induce nasal neutralizing antibodies
Allergy ( IF 12.4 ) Pub Date : 2021-09-20 , DOI: 10.1111/all.15101
Jozefien Declercq 1, 2, 3 , Els Tobback 4 , Stijn Vanhee 2, 3 , Natalie De Ruyck 1 , Sarah Gerlo 5, 6 , Philippe Gevaert 1 , Linos Vandekerckhove 3, 4, 5
Affiliation  

To date, several vaccines against severe acute respiratory coronavirus 2 (SARS-CoV-2) have proven to effectively reduce severe illness.1, 2 To promote herd immunity and reduce virus circulation, vaccines need to effectively reduce transmission risk. The nasal cavity is the first entrance point for SARS-CoV-2, and it has been suggested that viral replication is most efficient in the upper airways.3 Local neutralizing antibodies (NAbs) in the nasal mucosa can play an important role in preventing SARS-CoV-2 infection and transmission by limiting viral replication and shedding. While induction of systemic neutralizing humoral responses has been shown for both natural infection and upon vaccination with BNT162b2 and ChAdOx1, the presence of NAbs in the nasal mucosa upon vaccination remains unclear. A recent not peer-reviewed report described the potential of BNT162b2 to induce NAbs in the nasal cavity, but did not consider prior COVID-19 as a potentiator of this response.4 Local humoral responses after vaccination with viral vector-based vaccines, another type of frequently used SARS-CoV-2 vaccines, have not been investigated. In the present study, we compared systemic and local immune responses in the serum and nasal secretions of 46 study subjects vaccinated with SARS-CoV-2 mRNA (BNT162b2) or viral vector-based (ChAdOx1) vaccines.

Serum and nasal secretions from subjects visiting the COVID-19 vaccination center at the University Hospital Ghent, Belgium were collected, just prior to the first SARS-CoV-2 vaccination and after the second dose of the same vaccine. Median time between second vaccine dose and sampling was 19 days (IQR: 15–23) for the BNT162b2 group and 18 days (IQ: 15–26) for the ChAdOx1 group. Collection of nasal secretions was performed as described previously.5 SARS-CoV-2 NAbs in serum and nasal secretions were determined using the Elabsciene SARS-CoV-2 Neutralization Antibody ELISA kit (Gentaur) as per manufacturer's instructions. This surrogate virus neutralization test uses purified receptor-binding domain (RBD) from the S protein and the host cell receptor ACE2 to mimic the virus-host interaction.6 This RBD-ACE2 interaction is blocked by SARS-CoV-2 specific NAbs in patient samples. Inhibition rates are calculated based on the OD value of the negative control. A cutoff of 20% inhibition is determined as positive for the presence of NAbs by the manufacturer, based on testing 500 negative control sera.

Forty-six subjects, mainly females, were included in the study (Table 1). Twenty-four subjects were vaccinated with BNT162b2 and 22 with ChAdOx1. In both groups, half of the study subjects had a history of prior COVID-19. NAbs were determined in serum and nasal secretions prior and post-vaccination in all study subjects. Prior to vaccination, 16 subjects had NAbs in serum and 4 in nasal secretions. At second sampling, except for one, all subjects showed NAbs in their serum, regardless of the vaccine received (Figure S1). In nasal secretions, NAbs were observed in the majority of subjects (n = 23; 96%) vaccinated with BNT162b2 and in about half of the subjects (n = 13; 59%) vaccinated with ChAdOx1 at second sampling (= 0.0032; Fisher's exact test) (Figure 1A). Moreover, the ACE2 binding inhibition in nasal secretion was higher in subjects vaccinated with BNT162b2 compared to those vaccinated with ChAdOx1 (< 0.0001; 2-way repeated-measures ANOVA with Sidak's multiple comparisons test) (Figure 1D). Induction of NAbs occurred irrespective of prior SARS-CoV-2 infection or the presence of patient-reported allergy to aeroallergens (pollen, animals and house dust mite) (Figure 1C-F).

TABLE 1. Subject baseline characteristics
BNT162b2 ChAdOx1
No (%) No (%)
n= 24 22
Sex
Female 18 (75%) 18 (82%)
Male 6 (25%) 4 (18%)
Age, median (IQR), y 42.5 (38.5–49.0) 36.0 (25.0–42.0)
BMI, median (IQR), kg/m2 25.0 (23.0–27.1) 23.7 (20.6–26.5)
Current smoking 1 (4%) 2 (9%)
Prior COVID-19 infection 12 (50%) 11 (50%)
Confirmed by RT-PCR 9 (75%) 10 (91%)
Confirmed by serology 1 (8%) 1 (9%)
Self-reported 2 (17%) 0 (0%)
Patient-reported allergy to aeroallergens
Yes 8 (33%) 5 (23%)
No 16 (67%) 17 (77%)
image
FIGURE 1
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Effect of SARS-CoV-2 vaccination on the induction of nasal neutralizing antibodies. A-B, Percentage of patients with SARS-CoV-2 neutralizing antibodies (A) and ACE2 binding inhibition rates (B) in nasal secretions prior and post-vaccination with BNT162b2 and ChAdOx1. (C-E), Percentage of patients with SARS-CoV-2 NAbs (C, E) and ACE2 binding inhibition rates (D, F) post-vaccination in nasal secretions of patients respective to prior COVID-19 (C, D) and to allergy to aeroallergens (E,F). Asterisks indicate statistical significance by two-way repeated-measures ANOVA followed by Sidak's multiple comparisons test for B and by ordinary two-way ANOVA with Tukey's multiple comparisons test for D and F. *< 0.05, **< 0.001, ***< 0.0002, ****< 0.0001

Taken together, our study shows that both BNT162b2 and ChAdOx1 vaccines can induce nasal NAbs, albeit variable in the ChAdOx1 arm. Why only some subjects develop local NAbs in the former group is currently unclear. Differences in time between the two vaccine doses or other mechanisms of action of the vaccines might account for the observed differences. Further research is needed to fully understand the underlying immunological mechanisms. Longitudinal follow-up of the described subjects is needed to see whether vaccines can induce long-lasting neutralizing responses in the nasal mucosa. Failure to induce long-lasting NAbs warrants rational booster design or other strategies, such as nasal vaccination. Based on our findings and given that mucosal NAbs might be key to prevent infection and viral shedding, we advocate for the inclusion of nasal mucosa NAbs measurements in vaccine efficacy trials and routine testing procedures.



中文翻译:

用 BNT162b2 和 ChAdOx1 疫苗接种 COVID-19 疫苗有可能诱导鼻中和抗体

迄今为止,已证明几种针对严重急性呼吸道冠状病毒 2 (SARS-CoV-2) 的疫苗可有效减少严重疾病。1, 2为促进群体免疫和减少病毒传播,疫苗需要有效降低传播风险。鼻腔是 SARS-CoV-2 的第一个入口点,有人认为病毒复制在上呼吸道最有效。3鼻粘膜中的局部中和抗体 (NAb) 可通过限制病毒复制和脱落,在预防 SARS-CoV-2 感染和传播中发挥重要作用。虽然自然感染和用 BNT162b2 和 ChAdOx1 疫苗接种后都显示了全身中和体液反应的诱导,但疫苗接种后鼻粘膜中 NAb 的存在仍不清楚。最近一份未经同行评审的报告描述了 BNT162b2 在鼻腔中诱导 NAb 的潜力,但并未将之前的 COVID-19 视为这种反应的增强剂。4尚未研究使用基于病毒载体的疫苗(另一种常用的 SARS-CoV-2 疫苗)接种后的局部体液反应。在本研究中,我们比较了 46 名接种 SARS-CoV-2 mRNA (BNT162b2) 或基于病毒载体的 (ChAdOx1) 疫苗的研究对象的血清和鼻腔分泌物中的全身和局部免疫反应。

在第一次 SARS-CoV-2 疫苗接种之前和第二剂相同疫苗之后,收集了访问比利时根特大学医院 COVID-19 疫苗接种中心的受试者的血清和鼻分泌物。BNT162b2 组第二次疫苗接种和取样之间的中位时间为 19 天(IQR:15-23),ChAdOx1 组为 18 天(IQ:15-26)。如前所述进行鼻分泌物的收集。根据制造商的说明,使用Elabsciene SARS-CoV-2 中和抗体 ELISA 试剂盒 (Gentaur) 测定血清和鼻腔分泌物中的 5 种 SARS-CoV-2 NAb。这种替代病毒中和测试使用来自 S 蛋白和宿主细胞受体 ACE2 的纯化受体结合域 (RBD) 来模拟病毒与宿主的相互作用。6这种 RBD-ACE2 相互作用被患者样本中的 SARS-CoV-2 特异性 NAb 阻断。根据阴性对照的 OD 值计算抑制率。基于对 500 份阴性对照血清的测试,制造商将 20% 抑制的截止值确定为存在 NAb 阳性。

该研究包括 46 名受试者,主要是女性(表 1)。24 名受试者接种了 BNT162b2,22 名受试者接种了 ChAdOx1。在两组中,一半的研究对象有既往 COVID-19 病史。在所有研究对象接种疫苗之前和之后,在血清和鼻腔分泌物中测定了 Nabs。在接种疫苗之前,16 名受试者的血清中含有 NAb,4 名鼻分泌物中含有 NAb。在第二次采样时,除了一个之外,所有受试者的血清中都显示出 NAb,无论是否接种了疫苗(图 S1)。在鼻分泌物中,在大多数 接种 BNT162b2的受试者( n = 23;96%)和大约一半的受试者( n  = 13;59%)在第二次采样时(= 0.0032; Fisher 精确检验)(图 1A)。此外,与接种 ChAdOx1 的受试者相比,接种 BNT162b2 的受试者的鼻分泌物中的 ACE2 结合抑制更高( < 0.0001;使用 Sidak 多重比较检验的 2 路重复测量 ANOVA)(图 1D)。无论之前是否感染过 SARS-CoV-2 或是否存在患者报告的对气源性过敏原(花粉、动物和屋尘螨)过敏的情况,都会发生 Nabs 的诱导(图 1C-F)。

表 1.受试者基线特征
BNT162b2 ChAdOx1
不 (%) 不 (%)
n = 24 22
性别
女性 18 (75%) 18 (82%)
男性 6 (25%) 4 (18%)
年龄,中位数(IQR),y 42.5 (38.5–49.0) 36.0 (25.0–42.0)
BMI,中位数 (IQR),kg/m2 25.0 (23.0–27.1) 23.7 (20.6–26.5)
目前吸烟 1 (4%) 2 (9%)
先前的 COVID-19 感染 12 (50%) 11 (50%)
通过 RT-PCR 确认 9 (75%) 10 (91%)
血清学证实 1 (8%) 1 (9%)
自我报告 2 (17%) 0 (0%)
患者报告对气源性过敏原过敏
是的 8 (33%) 5 (23%)
16 (67%) 17 (77%)
图片
图1
在图形查看器中打开微软幻灯片软件
SARS-CoV-2疫苗对鼻中和抗体诱导的影响。AB,BNT162b2 和 ChAdOx1 疫苗接种前后鼻分泌物中 SARS-CoV-2 中和抗体 (A) 和 ACE2 结合抑制率 (B) 的患者百分比。(CE),与既往 COVID-19(C、D)和对气源性过敏原 (E,F) 过敏。星号表示通过双向重复测量方差分析,然后是 Sidak 对 B 的多重比较检验和普通双向方差分析,对 D 和 F 进行 Tukey 的多重比较检验。 * < 0.05,** < 0.001,** * < 0.0002, **** < 0.0001

总之,我们的研究表明,BNT162b2 和 ChAdOx1 疫苗都可以诱导鼻 NAb,尽管在 ChAdOx1 臂中有所不同。为什么只有一些受试者在前一组中产生局部 NAb,目前尚不清楚。两种疫苗剂量或疫苗的其他作用机制之间的时间差异可能是观察到的差异的原因。需要进一步研究以充分了解潜在的免疫机制。需要对所述受试者进行纵向随访,以了解疫苗是否可以在鼻粘膜中诱导持久的中和反应。未能诱导长效 NAbs 需要合理的加强剂设计或其他策略,例如鼻腔疫苗接种。根据我们的发现并考虑到黏膜 NAbs 可能是预防感染和病毒脱落的关键,

更新日期:2021-09-20
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