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Introduction
Whereas individual use of antibody (Ab) tests has shown very limited value during the Covid-19 pandemic, population serological surveys have proven usefulness to characterize relevant epidemiological parameters and to guide public health strategies against COVID-19.1 As of October 2022, in the Valencian Community, Spain, with around five million inhabitants, 94% of the population aged 12 and over was fully vaccinated, and 58% had a booster vaccination administered (about 95% in the over 60s).2 Until that month, the Valencian Community had reported around 1.6 million SARS-CoV-2 infection cases (almost a third of the population),3 yet the cumulative incidence of infection may be underestimated due to the large proportion of asymptomatic people and the reduction in testing after the emergence of Omicron. A population serosurvey in April 2022 showed that at least 52% of the Valencian Community population had been infected.4
Few serosurvey studies involving the general population and extending into the Omicron BA.5 wave have been published.5,6 As a part of the ProVaVac Valencian COVID-19 vaccine research program launched by the Valencian Community Government in March 2021, we conducted a population-based study aimed primarily at estimating the seroprevalence of SARS-CoV-2 Ab in the general Valencian Community population in October 2022, when BA.5 was the predominant variant in Spain.
Methods
Design and setting
Cross-sectional, region-wide, population-based study using residual blood samples, conducted in randomly selected primary care centers (PCC) of the Valencian Health System in October 2022. The Valencian Health System, part of the Spanish National Health System,7 is an extensive network of public hospitals, more than 200 PCC and public health structures funded and mostly provided by the Valencian Government, which covers about 97% of the Valencian Community population. The Valencian Health System information system use a single personal identification number allowing the link of several publicly owned population-based healthcare integrated databases8 with comprehensive clinical, laboratory and administrative information for the Valencian Community inhabitants, including the Valencian Microbiology (MiVa) Network, a microbiology registry from all public Valencian Community laboratories with data of COVID-19 Active Infection Diagnostic Tests [AIDT] from all public and private laboratories (including antigen rapid test carried out at PCC, accident & emergency departments or pharmacies, but not those performed at home) and the population vaccination registry, which includes all vaccinations administered in the Valencian Community and data from residents vaccinated in other regions.
Sample obtention
The sample was randomly selected and stratified proportionally to the age-sex distribution of the Valencian Community population (oversampling the age 0-9 years and 80 and over groups and reducing of the 35-49 and 50-64 years groups) and distributed in 88 PCC (randomized, among those 202 PCC with more than 7000 assigned people, to simplify logistics) according to the size of the population served in each one of them. Sample size was determined at 1127 participants (around ± 2% precision assuming a prevalence of anti-N Ab of 75% and a confidence level of 90%). Samples were obtained from an additional 5ml tube collected from patients having blood drawn on doctor's orders for any reason and meeting the age/sex selection criteria assigned to each PCC. A total of 787 samples were received (response rate: 69.8%). Two samples could not be linked to patient data, leaving 785 samples for statistical analysis. 66% of the losses corresponded to people under 20 years old (not enough youngers with laboratory tests ordered on the day of sampling at the selected PCC). Other losses were due to local holidays or failure to collect lab samples by the PCC on the assigned day.
Ethics
Requirement for informed consent was waived by the Valencian Research Ethics Committee of Public Health (ref. 20220408/02) because the project was developed under the epidemiological surveillance competences of the Valencian Community Department of Health.
Analysis
According to vaccination status from the vaccination registry, SARS-CoV-2 infection recorded before recruitment, and the results of SARS-CoV-2 Ab assays, participants were grouped into four categories (Table 1): vaccinated/experienced (Vac-Exp), vaccinated/naïve (Vac-Naïve), unvaccinated/experienced (UnVac-Exp) and unvaccinated/naïve (UnVac-Naïve). SARS-CoV-2-RBD-total antibodies and nucleocapsid (N)-reactive IgG antibodies were measured in sera using the Roche Elecsys® anti-SARS-CoV-2 S and Elecsys® anti-SARS-CoV-2N assays (Roche Diagnostics, Pleasanton, CA, USA), respectively, following the manufacturer's recommendations. Age-sex proportions with 95% confidence intervals (95%CI) were estimated. Since no significant differences were found between men and women (see Tables I and II in online Appendix), results are shown by age strata. Total results were weighted by the proportion of Valencian Community population in each age/sex stratum. The analyses were performed using STATA 17.0 (StataCorp, College Station, Texas, USA).
Table 1. Classification of participants according to their vaccination status and recorded SARS-CoV-2 infection at the time of recruitment.
| Acronym | Anti-RBD | Vac Reg. | Anti-N | AIDT Reg. | Interpretation |
|---|---|---|---|---|---|
| UnVac-naïve | - | - | - | - | Unvaccinated naïve: No serological evidence of vaccine immunization [anti-RBD (−)] AND no recorded vaccination AND no serological evidence of previous infection [anti-N (−)] AND no previous positive AIDT recorded. |
| UnVac-Exp | - | - | + | Unvaccinated experienced: No serological evidence of vaccine immunization [anti-RBD (−)] AND no recorded vaccination AND (Serological evidence of previous infection [anti-N (+)] OR previous positive AIDT recorded). | |
| Vac-naïve | + | - | - | Vaccinated naïve: (Serological evidence of vaccine immunization [anti-RBD (+)] OR recorded vaccination) AND no serological evidence of previous infection [anti-N (−)] AND no previous positive AIDT recorded. | |
| Vac-Exp | + | + | Vaccinated experienced or hybrid immunity: (Serological evidence of vaccine immunization [anti-RBD (+)] OR recorded vaccination) AND (serological evidence of previous infection [anti-N (+)] OR previous AIDT recorded) |
AIDT Reg: Active Infection Diagnostic Test recorded in the MiVa Network Microbiology Register; Anti-N: nucleocapsid antibodies; Anti-RBD: receptor binding domain antibodies; Vac Reg: Vaccination Registry.
Results
Of the weighted sample, 90.4% was vaccinated with at least one dose (see Table III in online Appendix). By age, all groups were above 90% except the 0-9 years old group (those under 6 were not candidates for vaccination). 59.2% of the weighted sample and more than 90% of people over 65 years had at least one booster dose. 30.6% of the weighted sample had a previous positive AIDT result registered on the MiVa Network, of which 8.1% had no detectable anti-N Ab.
Of the weighted sample, 98.4% maintained detectable RBD Ab against SARS-CoV-2, either due to vaccination or infection (Table 2). Even in the 0-9 age group, the proportion exceeds 90%. Of the weighted sample, 71% maintained detectable anti-N Ab, with higher figures in youngers (>80% between 10 and 34 years) than in those 65 and over (around 50%). When adding patients with at least one positive AIDT registered, 74.6% of the weighted sample had been infected at some point by SARS-CoV-2. 66.7% were Vac-Exp, 23.7% were Vac-Naïve and 7.9% were UnVac-Exp; the remaining 1.7% were UnVac-naïve, mostly people under 10 years.
Table 2. Serological status and hybrid immunity in the Valencian Community, October 2022.
| n | RBD seroprevalence | Anti-N seroprevalence | PreviousaSARS-CoV-2 infection | Vaccinatedexperiencedb | Unvaccinated naïvec | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age strata | % | 95%CI | % | 95%CI | % | 95%CI | % | 95%CI | % | 95%CI | |||||||||||
| 0-9 | 56 | 91.1 | 80.4 | 97.0 | 75.0 | 61.6 | 85.6 | 76.8 | 63.6 | 87.0 | 37.5 | 24.9 | 51.4 | 14.3 | 6.4 | 26.2 | |||||
| 10-19 | 59 | 100.0 | 93.9 | 100 | 86.4 | 75.0 | 94.0 | 88.1 | 77.0 | 95.1 | 81.4 | 69.1 | 90.3 | 0.0 | 0.0 | 6.1 | |||||
| 20-34 | 118 | 99.2 | 95.4 | 99.9 | 85.6 | 77.9 | 91.4 | 88.1 | 80.9 | 93.3 | 79.7 | 71.3 | 86.5 | 0.8 | 0.0 | 4.6 | |||||
| 35-49 | 145 | 98.6 | 95.1 | 99.8 | 68.3 | 60.0 | 75.7 | 74.5 | 66.6 | 81.4 | 69.0 | 60.8 | 76.4 | 0.0 | 0.0 | 2.5 | |||||
| 50-64 | 156 | 100.0 | 97.7 | 100 | 71.2 | 63.4 | 78.1 | 75.0 | 67.4 | 81.6 | 71.2 | 63.4 | 78.1 | 0.6 | 0.0 | 3.5 | |||||
| 65-79 | 140 | 97.9 | 93.9 | 99.6 | 56.4 | 47.8 | 64.8 | 59.3 | 50.7 | 67.5 | 57.9 | 49.2 | 66.1 | 0.7 | 0.0 | 3.9 | |||||
| 80+ | 111 | 98.2 | 93.6 | 99.8 | 45.9 | 36.4 | 55.7 | 48.6 | 39.0 | 58.3 | 43.2 | 45.0 | 54.8 | 1.8 | 0.2 | 6.3 | |||||
| Total weighted | 785 | 98.4 | 97.5 | 99.3 | 71.0 | 67.8 | 74.2 | 74.6 | 71.5 | 77.6 | 66.7 | 63.4 | 70.0 | 1.7 | 0.8 | 2.6 | |||||
95%CI: 95% confidence interval.
aPeople with anti-N Ab or a positive AIDT recorded.
bVaccinated people with anti-N Ab or a positive AIDT.
cNon-vaccinated not-infected people.
Discussion
As of October 2022, after the BA.1, BA.2 and BA.5 waves,3 three out of four people in the Valencian Community had been infected and two out of three had hybrid immunity, although less than one in three had a positive AIDT registered in the MiVa Network. Differences with the serosurvey of April 2022 (anti-N: 47.9%; Vac-exp: 51.9)4 indicate a high transmission during spring and summer 2022, when around 25% of the Valencian Community population became infected (see Table IV in online Appendix). These results are consistent with seroprevalence studies carried out after the BA.2 wave in British Columbia (Canada)5 and Geneva (Switzerland),6 with figures between 61% and 72% for anti-N seroprevalence.
Our study has some limitations. First, people who have been ordered a lab tested may be different from the general population in propensity to infection. Second, we excluded PCC with less than 7000 people assigned, excluding a good part of rural areas, although these usually organize blood drawn in other most populated villages. And third, precision in the pediatric population was markedly reduced by the low number of lab orders in younger groups.
In summary, by October 2022 around three quarters of the Valencian Community population had been infected with SARS-CoV-2 and, due to extensive vaccination, most exhibited hybrid immunity. The high proportion of hybrid immunity is relevant from a public health perspective since these people foreseeably have better and longer lasting protection against the development of severe COVID-19.9,10 The relatively low proportion of hybrid immunity among the elderly advised for a second vaccination booster in people 65 and over.
What is known about the topic?
Few serosurvey studies involving the general population and extending into the Omicron BA.5 wave have been published. We conducted a population-based study to estimate the cumulative incidence of SARS-CoV-2 infection in the population of the Valencian Community, Spain.
What does this study add to the literature?
In October 2022, three out of four people in the Valencian Community had been infected and two out of three had hybrid immunity. Compared to April 2022, results indicate a high transmission during spring/summer, when around 25% of the population became infected.
Transparency declaration
The corresponding author on behalf of the other authors guarantee the accuracy, transparency and honesty of the data and information contained in the study, that no relevant information has been omitted and that all discrepancies between authors have been adequately resolved and described.
