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Clinic Unit of Clinic Laboratories, Immunology Laboratory, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital (HUVR)/CSIC/University of Seville, Ave. Manuel Siurot s/n, 41013, Seville, Spain
Clinic Unit of Clinic Laboratories, Immunology Laboratory, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital (HUVR)/CSIC/University of Seville, Ave. Manuel Siurot s/n, 41013, Seville, Spain
Clinic Unit of Clinic Laboratories, Immunology Laboratory, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital (HUVR)/CSIC/University of Seville, Ave. Manuel Siurot s/n, 41013, Seville, Spain
Clinic Unit of Clinic Laboratories, Immunology Laboratory, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital (HUVR)/CSIC/University of Seville, Ave. Manuel Siurot s/n, 41013, Seville, Spain
Clinic Unit of Clinic Laboratories, Immunology Laboratory, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital (HUVR)/CSIC/University of Seville, Ave. Manuel Siurot s/n, 41013, Seville, SpainImmunology Service, Virgen del Rocío University Hospital (HUVR), Seville, Spain
Immunovirology Unit, Internal Medicine Service, Viamed Hospital, Santa Ángela de la Cruz, Seville, SpainHogar Residencia de la Santa Caridad, Seville, Spain
Clinic Unit of Clinic Laboratories, Immunology Laboratory, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital (HUVR)/CSIC/University of Seville, Ave. Manuel Siurot s/n, 41013, Seville, Spain
Hence, many countries have considered the administration of booster doses of vaccines due to the lower levels of anti-S IgG antibodies achieved by elderly adults after two doses of vaccine and a faster waning immunity thereafter.
showing anti-SARS-CoV-2 antibodies before and after the third dose of the vaccine, reported that elderly adults achieved similar levels of anti-S IgG titers after the booster dose than those achieved by younger participants, shedding light on the benefit of the administration of such vaccine booster. Here, we present additional longitudinal data reinforcing this concept.
We designed a prospective study including residents and health workers from the “Santa Caridad Elderly Home” (Seville, Spain) who provided blood samples one month after receiving the second dose of the BNT162b2 vaccine (T1), and also, four (T4) and eight (T8) months later. Additional third dose of BNT162b2 vaccine was administered 1–2 days after T8, and samples were taken one month later (T9) (Fig. 1A). Subjects with previous COVID-19 diagnosis, under immunosuppressive therapy or without available samples at both, T1 and T9 were excluded from the analysis. The study was approved by the Research Ethics Committee of our hospital (PEIBA Acta CEI_02/2021) and written informed consent was obtained for all participants. Anti-S IgG antibodies against trimeric SARS-CoV-2 Spike protein were quantified by chemiluminescence (LIAISON® SARS-CoV-2 TrimericS IgG), showing good correlation with microneutralization test.
Positive results were considered ≥33.8 BAU/mL (additional information in supplementary material).
Sixty-one subjects were finally included in the study and were subdivided in two groups attending to age: (i) elderly group, including subjects over 65 years-old (n = 40) and (ii) young group, including participants under such age (n = 21). Demographics, anthropometrics and humoral titer values are summarized in Table 1. Older participants were all men 40 (100%), with a median age of 78 years-old. The median age for the young group was 49 years-old and nine (42.9%) were men. The dynamics of anti-S IgG titers along time for elderly and young participants are represented in Fig. 1B . Anti-S IgG titers were significantly lower in elderly participants at all time-points of the study, except at T9 (one month after the booster dose), where the antibody levels were similar between both study groups (Fig. 1C). After the first two doses of the vaccine, a declining of antibody titers along time was observed in all participants without exceptions. The median antibody loss was 73% and 91% between T1-T4 and T1-T8, respectively, in the elderly group. In the younger group, the loss of anti-S IgG titers was similar, with a median loss of 70% between T1-T4 and 92% between T1-T8. The rate of positive response declined from 100% at T1 to 92% at T4, and to 75% at T8 in older participants. However, the decline in the rate of positive response was delayed in younger participants, that maintained 100% of seroconversion at T4, declining thereafter to 89% at T8. Then, a booster effect was observed in all participants following the administration of the booster dose (T9), showing all of them positive responses at this time point. Thus, anti-S IgG titers had approximately 7-fold and 54-fold increase in older participants respect to T1 and T8, respectively (p < 0.001). Besides, younger participants showed a 4-fold and 49-fold increase respect to T1 and T8, respectively (p < 0.001). Remarkably, elderly group showed a no significant trend to higher increase in anti-S titers between T1 and T9 than younger adults (p = 0.105) (Fig. 1D).
Table 1Demographics, anthropometrical and anti-S IgG titers of the study populations.
Characteristic
Elderly Group (N = 40)
Young Group (N = 21)
p
Demographics
Age, median [IQR], years
78 [74–83]
49 [40–62]
<0.001
Sex (men)
40 (100)
9 (42.9)
<0.001
BMI, median [IQR]
27 [25.8–31.5]
27.6 [23.6–30.7]
0.461
IgG titer (BAU/mL)
T1, median [IQR]
1185 [777–1635]
1980 [1215–2490]
<0.001
T4, median [IQR]
259 [142–473]
611 [336–1100]
<0.001
T8, median [IQR]
108 [46–158]
219 [80–274]
0.011
T9, median [IQR]
6910 [3295–14,930]
8220 [4910–13,820]
0.239
Increase in IgG titer (fold change)
T1-T9, median [IQR]
6.9 [3.7–10.1]
4.2 [2.9–7.7]
0.105
Categorical variables are represented as N (%) and continuous variables as median [IQR]. Mann Whitney U-test was used for comparisons between continuous variables, and Chi-square test for comparisons between categorical variables. p values < 0.05 were considered statistically significant. BMI, body mass index, calculated as weight (kilograms) divided by height (meters squared); BAU, Binding Arbitrary Units; T1, one month after the second dose; T4, four months after the second dose; T8, eight months after the second dose; T9, one month after the third dose.
Fig. 1(A) Schematic representation of the administration of the BNT162b2 vaccine. (B) Long-term longitudinal follow-up of antibody IgG titers in elderly and young groups vaccinated with three doses of the BNT162b2 vaccine. T1, one month after the second dose; T4, four months after the second dose; T8, eight months after the second dose; T9, one month after the third dose. Friedman test and Bonferroni adjustment to a series of post hoc Wilcoxon matched pairs tests were applied. Except for Bonferroni correction (p < 0.008), p-values < 0.05 were considered statistically significant. **Wilcoxon test p < 0.001 for all paired-comparisons. (C) Comparison of anti-S IgG titers between study groups at T1 (one month after the second dose), T4 (four months after the second dose), T8 (eight months after the second dose and 1–2 days before the administration of the third dose) and T9 (one month after the third dose). The Mann Whitney U test was applied for comparisons between study groups at all-time points, considering p values < 0.05 statistically significant. (D) Comparison of the fold-increase of anti-S IgG titers between T1-T9 between study groups. Comparisons were made using the Mann Whitney U-test and p values < 0.05 were considered statistically significant.
Accordingly, we found strong negative correlations between the anti-S antibodies achieved at T1, T4 and T8 and the age of participants (r = −0.479, p < 0.001, r = −0.425, p = 0.001 and r = −0.356, p = 0.006, respectively), whereas such correlation was completely absent at T9 (r = −0.058, p = 0.657). When considering only men in the younger group, all the results showed the same trends.
In our study, we found that anti-S antibodies achieved one month after the third dose of the BNT162b2 vaccine were similar between elderly and young participants. Longitudinal follow-up from this time-point is needed to assess if the loss of titers will then depend on age, as it occurred after the earlier doses of vaccine. According to our data, a recent report on a cohort of nursing home residents over 60 years,
reported that a third BNT162b2 dose significantly increases IgG titers and that such titers were not associated with age. Our results are also in accordance with those recently reported by Dimeglio et al.,
that found similar levels of anti-S titers after the third dose in elderly and young vaccinees. On the contrary, a poorer response after the third dose in older adults has been also recently reported in this journal.
However, it was only observed in octogenarian and nonagenarian participants, and age resulted not to be independently associated with poor responses in a multivariate analysis. Moreover, in this study, contrary to ours, several participants resulted non responder to the booster dose, perhaps because it included a high proportion of very old subjects and because the humoral response was determined by a point-of-care fingertip whole blood testing, which could be less sensitive.
Our longitudinal design, also covering the response to previous doses of vaccine, allowed us to note that the age of the participants negatively affected the levels of anti-S IgG antibodies achieved after the first two doses of vaccine, but not after the third dose, suggesting that primary vaccination protocol of such risk population of elderly people should include three doses. In this sense, the vaccination protocol in vulnerable clinical settings, such as patients under immunosuppressive therapies or oncology patients, already considers three doses as their primary vaccination protocol.
María del Mar Pozo-Balado: Conceptualization, Formal analysis, Investigation, Writing – original draft. Ángel Bulnes-Ramos: Formal analysis, Investigation, Writing – original draft. Vanesa Garrido-Rodríguez: Investigation. Israel Olivas-Martínez: Investigation. Carmen Lozano: Investigation. María Francisca González-Escribano: Resources. Manuel Leal: Resources. Yolanda M Pacheco: Funding acquisition, Conceptualization, Supervision, Writing – review & editing.
Declaration of Competing Interest
None to disclose.
Acknowledgments
We thank all residents for their collaboration and Rafael Martínez Alba, MSc, director of the “Residencia Hogar de la Santa Caridad”, for allowing us to perform the study in this institution. We also thank Juan Antonio Santamaría, BSc, and Rafael Bernal, BSc, registered nurses at the “Residencia Hogar de la Santa Caridad” for their clinical assistance. None of the above individuals were compensated for their contributions.
Funding
This work was supported by the Instituto de Salud Carlos III through the project “PI21/00357” (Co-funded byEuropean Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”). MMPB was supported by a postdoctoral contract from Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía (DOC_01646). ABR, IOM and VGR were supported by Instituto de Salud Carlos III (Sara Borrell program CD19/00143, Rio Hortega program CM19/00051, and PFIS program FI19/00298, respectively). YMP was supported by the Consejería de Salud y Familias of Junta de Andalucía through the ‘‘Nicolás Monardes’’ program (RC‐0006-2021).
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