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Microbiology Service, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, SpainCentro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
1 Senior authors that contributed equally to the current work.
Affiliations
Microbiology Service, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, SpainCentro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, SpainDepartment of Microbiology, School of Medicine, University of Valencia, Valencia, Spain
We read with interest the study published by Dimeglio et al. in the Journal of Infection showing that SARS-CoV-2 Omicron BA.1 breakthrough infection following receipt of two or three COVID-19 vaccine doses elicits a stronger homotypic (BA.1) neutralizing antibody (NtAb) response than vaccination alone in the general population.
In this study most recruited individuals were young (median age, 39 years) and NtAb measurements (using a live SARS-CoV-2 Omicron BA.1 isolate) were performed soon after receipt of the last vaccine dose (between 3 and 6 weeks). Omicron BA.1 has been long displaced worldwide by several Omicron sublineages, including Omicron BA.4/5 which display an increased ability to evade NtAb responses elicited by Wuhan-Hu-1 vaccine platforms compared to BA.1.
to show that long after full or booster vaccination (median, 287 days; IQR, 260–332), SARS-CoV-2 experienced individuals exhibit more robust NtAb responses against Omicron BA.4/5 than their vaccinated SARS-CoV-2 naïve counterparts, regardless of whether infection was due to Wuhan-Hu-1, Omicron BA.1 or Omicron BA.2 variants.
Sera from a total of 130 individuals (62 males/68 females; median age, 56 years; IQR, 34–72) were analyzed as described below. Individuals were randomly selected from a total of 787 participants in a SARS-CoV-2 seroprevalence cross-sectional, region-wide, population-based study that was conducted in the primary care zones of the Valencian Community (VC) in (Spain) during October of 2022 (unpublished results), as described in an analogous study conducted in April 2022.
The requirement for informed consent was waived by the Research Ethics Committee of Public Health (ref. 20,220,408/02) since the project was developed under the epidemiological surveillance competencies of the VC Ministry of Health (Law 10/2014 of the Valencian Community on Public Health).
Out of the 130 participants, 91 were categorized as SARS-CoV-2 experienced (VAC-ex) upon detection of anti-SARS-CoV-2 nucleocapsid protein IgG antibodies (Elecsys® Anti-SARS-CoV-2 N assays; Roche Diagnostics, Pleasanton, CA, USA). Twenty-two out of the 91 had a record of a positive RT-PCR assay in nasopharyngeal specimens [VC microbiology registry (RedMiVa)]. The remaining 39 participants were deemed as SARS-CoV-2 naïve (VAC-n), as they lacked anti-N IgGs and had no record of prior infection. As shown in Table 1, VAC-ex and VAC-n participants were matched by sex, vaccine platform employed, receipt of a booster dose, type of booster (homologous vs. heterologous), and the time elapsed since the last vaccine dose. Nevertheless, participants in the VAC-n group were significantly younger (P<0.007). NtAbs were measured using a GFP-expressing vesicular stomatitis virus pseudotyped with the Wuhan-Hu-1 or Omicron BA.4/5 spike (S) protein, as previously described.
Severe acute respiratory syndrome coronavirus 2 adaptive immunity in nursing home residents following a third dose of the comirnaty coronavirus disease 2019 vaccine.
The BA.4/5 spike was cloned into a pCG1 vector using a codon-optimized Omicron BA.4/5 S expression plasmid obtained from Addgene (Catalog number 186,031) as the template. Both constructs used lacked the terminal 19 amino acid residues to improve pseudotyping efficiency. Neutralization assays were performed as previously described,
Severe acute respiratory syndrome coronavirus 2 adaptive immunity in nursing home residents following a third dose of the comirnaty coronavirus disease 2019 vaccine.
except VeroE6/TMPRSS2 cells (JCRB Cell bank catalog code: JCRB1819) were used. Sera testing negative (undetectable) were arbitrarily ascribed a titer of 1/20. Most VAC-ex (100%) and VAC-n (94.7%) participants exhibited detectable NtAb responses against the Wuhan-Hu-1 variant (P = 0.30). In contrast, the percentage of VAC-n individuals displaying detectable NtAb against Omicron BA.4/5 was significantly lower than that for VAC-ex (52.6% vs. 98.9%; P<0.001). Overall, as shown in Fig. 1A, NtAb titers against Omicron BA.4/5 were significantly lower than that against Wuhan-Hu-1 in both VAC-ex (median inverse reciprocal titer for BA.4/5 and Wuhan-Hu-1, respectively of 1462; IQR,536–4803 vs. 11,398; IQR, 4652–62,500; P<0.001) and VAC-n (median, 24 IQR,10–204, vs. 1504; IQR, 565–6883; P<0.001). Nevertheless, compared to VAC-n, VAC-ex exhibited significantly higher NtAb titers against both Wuhan-Hu-1 (7-fold; P<0.001) and Omicron BA.4/5 (61-fold; P<0.001), irrespective of whether participants receiving a regular vaccine schedule or boostered with an additional vaccine dose were analyzed separately (not shown).
Fisher's exact test or Mann-Whitney U test, as appropriate. Two-sided exact P-values are reported. A P-value <0.05 was considered statistically significant. The analyses were performed using SPSS version 20.0 (SPSS, Chicago, IL, USA) and STATA 17.0 (StataCorp, College Station, Texas, USA).
Sex: no. male/female (%)
42/49 (46/54)
20/19 (51/49)
0.99
Age (median years, IQR)
70 (31–67)
51 (48–82)
0.007
0–9
3 (3.3%)
2 (5.1%)
10–19
8 (8.8%)
1 (2.6%)
20–34
19 (20.9%)
2 (5.1%)
35–49
14 (15.4%)
7 (18%)
50–64
21 (23%)
5 (12.8%)
65–79
20 (22%)
9 (23%)
80
6 (6.6%)
13 (33.3%)
Vaccine platform: no. (%)
0.91
mRNA Comirnaty® (BioNTech /Pfizer)
54 (59)
29 (74)
mRNA Spikevax® (Moderna / Lonza)
16 (17.6%)
5 (12.8)
Viral Vector Vaxzevria® (Oxford / AstraZeneca)
15 (16.5)
2 (5)
Viral Vector Jcovden® (JandJ / Janssen)
5 (5)
3 (7.7)
Inactivated CoronaVac® (Sinovac Biotech)
1 (1)
0
Number of vaccine doses: no. (%)
0.99
One
2 (2.20)
1 (2.6)
Two
25 (27.5)
10 (25.6)
Three
62 (68)
28 (71.8)
Four
2 (2.2)
0
Receipt of a booster vaccine dose (Yes,%/No,%)
68 (75) /23 (25)
30 (77) /9 (23)
0.99
Type of booster: no. (%)
0.96
Homologous
28 (41)
15 (50)
Heterologous
40 (59)
14 (50)
Days elapsed since last vaccine dose (median, IQR)
283 (260–322)
307 (267–336)
0.09
a Fisher's exact test or Mann-Whitney U test, as appropriate. Two-sided exact P-values are reported. A P-value <0.05 was considered statistically significant. The analyses were performed using SPSS version 20.0 (SPSS, Chicago, IL, USA) and STATA 17.0 (StataCorp, College Station, Texas, USA).
Fig. 1Neutralizing antibody (NtAb) responses against Wuhan-Hu-1 and Omicron BA.4/5 as measured using a pseudotyped vesicular stomatitis virus system. (A) Reciprocal NtAb titers against Wuhan-Hu-1 and Omicron BA.4/5 in vaccinated/SARS-CoV-2 experienced (VAC-ex) and vaccinated/SARS-CoV-2 naïve participants (VAC-n). (B) Reciprocal NtAb titers against Wuhan-Hu-1 and Omicron BA.4/5 in vaccinated/SARS-CoV-2 experienced (VAC-ex) participants with SARS-CoV-2 infection documented by RT-PCR. P values for comparisons across groups (Mann-Whitney U test) are shown. A P value <0.05 was deemed as significant. The analyses were performed using SPSS version 20.0 (SPSS, Chicago, IL, USA) and STATA 17.0 (StataCorp, College Station, Texas, USA).
Out of the 22 VAC-ex individuals with a record of a positive SARS-CoV-2 RT-PCR assay, in 13 infection was documented during 2022 within waves dominated (≥95% of cases) by BA.1 (n = 6) and BA.2 (n = 7), and before the emergence of BA.4/5 in the VC; the remaining 9 individuals had contracted SARS-CoV-2 infection during 2020/2021, prior to the surge of the Omicron variant in the VC. Following the matching of individuals in both comparison groups according to the time elapsed from the receipt of the last vaccine dose, NtAb titers against Omicron BA.4/5, but not against Wuhan-Hu-1 (Fig. 1B), were significantly lower (P<0.001) in individuals that contracted SARS-CoV-2 infection prior to 2022. Importantly, VAC-n individuals displayed lower NtAb titers against both Wuhan-Hu-1 (P<0.01) and Omicron BA.4/5 (P<0.001) than VAC-ex, irrespective of when SARS-CoV-2 infection was documented. The current study has several limitations. First, the date of SARS-CoV-2 infection could only be documented in a small percentage of VAC-ex participants. Second, the SARS-CoV-2 lineages could not be confirmed by sequencing in cases with positive RT-PCR results. Third, whether participants that experienced COVID-19 due to Wuhan-Hu-1 were reinfected by Omicron BA.1 or BA.2 could not be ascertained. Fourth, due to the possibility of N-seroreversion some participants could have been miscategorized as being SARS-CoV-2 naïve. In summary, the main observation of our study was that long (median 287 days) after COVID-19 vaccination with full or booster regimens, VAC-ex individuals display a more robust NtAb response against Omicron BA.4/5 compared to VAC-n. Interestingly, although the difference across groups was more marked when participants contracting Omicron BA.1 or BA.2 infection were considered separately, it was also maintained for those that were infected with the ancestral SARS-CoV-2 Wuhan-Hu-1 variant or pre-Omicron variants of concern. Our observation agrees with data reported in several series comprising individuals vaccinated (either boostered or not) with mRNA or inactivated SARS-CoV-2-based COVID-19 vaccine platforms
and may help inform public health decision-making regarding COVID-19 vaccination policies for the near future.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Author contributions
JC, JZ, EG, LR, S V-A and EA, methodology and data validation. HV and RL participated in the implementation of the vaccine rollout program in the Valencian Community. SP, RG and DN, conceptualization and data analysis. RG and DN wrote the manuscript.
Funding
This work was supported in part by the European Commission NextGenerationEU fund, awarded to RG through CSIC's Global Health Platform (PTI Salud Global).
Data availability statement
The data presented in the manuscript have not been made available, but can be shared upon request.
Acknowledgments
We are grateful to the staff and nurses of primary care centers participating in this study. We also thank Ana Berenguer, General Director of Analysis and Public Policies of the Presidency of the Generalitat. Eliseo Albert (Juan Rodés Contract; JR20/00011) and Estela Giménez (Juan Rodés Contract, JR18/00053) hold contracts funded by the Carlos III Health Institute (co-financed by the European Regional Development Fund, ERDF/FEDER). Sebastian Velandia-Álvarez holds a Generalitat Valenciana Grisolia Ph.D. fellowship (CIGRIS/2021/080).
References
Dimeglio C.
Migueres M.
Chapuy-Regaud S.
Da-Silva I.
Jougla I.
Pradere C.
et al.
Comparative effects of mRNA vaccine booster and natural Omicron infection on the neutralizing antibody response.
Severe acute respiratory syndrome coronavirus 2 adaptive immunity in nursing home residents following a third dose of the comirnaty coronavirus disease 2019 vaccine.
Members of the Valencian vaccine research program (ProVaVac) study group: Vanaclocha Luna H (General Directorate of Public Health, Department of Health, Valencia Government, Valencia, Spain); Burks DJ (The Prince Felipe Research Center-CIPF-, Valencia, Spain; Cervantes A (INCLIVA Health Research Institute, Valencia, Spain); Comas I (Biomedicine Institute of Valencia, Spanish Research Council (CSIC); Díez-Domingo J (Foundation for the promotion of health and biomedical research of the Valencian Community-FISABIO-, Valencia, Spain); Peiro S (Foundation for the promotion of health and biomedical research of the Valencian Community-FISABIO-, Valencia, Spain); González-Candelas F (CIBER in Epidemiology and Public Health, Spain; Joint Research Unit "Infection and Public Health" FISABIO-University of Valencia, Valencia, Spain; Institute for Integrative Systems Biology (I2SysBio), CSIC-University of Valencia, Valencia, Spain); Ferrer Albiach C (Fundación Hospital Provincial de Castelló);Redón J (INCLIVA Health Research Institute, Valencia, Spain); Sánchez-Payá J (Preventive Medicine Service, Alicante General and University Hospital, Alicante, Spain; Alicante Institute of Health and Biomedical Research (ISABIAL), Alicante, 41,423.Spain; Sanz G (Instituto de Investigación Sanitaria La Fe); Sempere JM (Biotechnology Department, University of Alicante, Spain); Zapater Latorre E (Fundación Hospital General Universitario de València); Navarro D (Microbiology Service, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Department of Microbiology, School of Medicine, University of Valencia, Valencia, Spain).
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