key: cord-0703241-m1xfw85b
authors: Amraotkar, A. R.; Bushau-Sprinkle, A. M.; Keith, R. J.; Hamorsky, K. T.; Palmer, K. E.; Gao, H.; Rai, S. N.; Bhatnagar, A.
title: Comorbidities Diminish the Likelihood of Seropositivity After SARS-CoV-2 Vaccination
date: 2022-03-16
journal: nan
DOI: 10.1101/2022.03.15.22272432
sha: dd6644e3a5665f242d88eb90b051109a5f5d9e23
doc_id: 703241
cord_uid: m1xfw85b

Background: The impact of chronic health conditions (CHC) on serostatus post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is unknown. Methods: We assessed serostatus post-SARS-CoV-2 vaccination among fully vaccinated participants recruited between April 2021 through August 2021 in 18 years and older residents of Jefferson County, Kentucky, USA. Serostatus was determined by measuring SARS-CoV-2 Spike protein specific immunoglobulin (Ig) G (Spike IgG) antibodies via enzyme-linked immunoassay (ELISA) in peripheral blood samples. Results: Of the 5,178 fully vaccinated participants, 51 were seronegative and 5,127 were seropositive. Chronic kidney disease (CKD) (OR=13.49; 95% CI: 4.88, 37.3; P<0.0001) and autoimmune disease (OR=11.34; 95% CI: 5.21, 24.69; P<0.0001) showed highest association with negative serostatus in fully vaccinated participants. The absence of any CHC was strongly associated with positive serostatus (OR=0.37; 95% CI: 0.19, 0.73; P=0.003). The risk of negative serostatus increased in the presence of two CHCs (OR=2.82; 95% CI: 1.14, 7) to three or more CHCs (OR=4.52; 95% CI: 1.68, 12.14). Similarly, use of 2 or more CHC related medications was significantly associated with seronegative status (OR=6.08; 95%: 2.01, 18.35). Conclusions: Presence of any CHC, especially CKD or autoimmune disease, increased the likelihood of seronegative status among individuals who were fully vaccinated to SAR-CoV-2. This risk increased with a concurrent increase in number of comorbidities, especially with multiple medications. Absence of any CHC was protective and increased the likelihood of a positive serological response post-vaccination. These results will help develop appropriate guidelines for booster doses and targeted vaccination programs.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its mutated variants continue to increase morbidity and mortality worldwide.(1) Congruent with infection prevention and control measures, wide-spread vaccination is an effective means of containing and ending the Coronavirus Disease 2019 pandemic. (2) However, in addition to the continued expansion of vaccination efforts, it is important to identify factors that impact vaccine efficacy.

Effectiveness of the vaccines among non-immunocompromised individuals in the US is documented. (3) But, there are sparse data comparing vaccine efficacy between individuals with and without pre-existing comorbidities, and their relative effect on vaccination response. Gaining insights into factors which affect the immunological response to vaccines will guide the deployment of boosters worldwide and help identify individuals at greater risk of breakthrough infections. Therefore, we sought to study the effect of comorbidities on serostatus post-SARS-CoV-2 vaccination.

Data for the study were collected under the Co-Immunity Project, which is a federally funded ongoing population-based study for the surveillance of SARS-CoV-2 in Jefferson County, Kentucky. The study was initiated in June 2020 and has completed 8 rounds of testing through 

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 For analysis, only fully vaccinated participants were included. As per the Centers for Disease Control and Prevention (CDC), participants were considered "Fully Vaccinated" only if their final dose (2 nd dose for Moderna or Pfizer-BioNTech and 1 st dose for Janssen) was >14 days prior to the study appointment.(4) All participants in this study were within 9 months of their final vaccination dose.

Health history regarding pre-existing chronic health conditions and medications was selfreported by the study participants. History of lupus, rheumatoid arthritis, celiac disease, spondylitis, graves disease, etc. was combined into a single variable "Autoimmune Diseases". Regular use of medications involved with immune-suppression like steroids, Secukinumab, Baricitinib, Tofacitinib, Methotrexate, etc. was combined into a single variable "Immunosuppressants". History of all modalities of cancer treatments including chemotherapy, radiation therapy, surgery, immunotherapy, etc. were combined into a single variable "Cancer Treatment". Use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blocker (ARB) was combined into a single variable "ACEi or ARB".

Trained staff collected nasopharyngeal swab and blood finger prick samples. Samples were analyzed for infection by reverse transcription polymerase chain reaction (RT-PCR). (5) Serostatus was determined by measuring levels of SARS-CoV-2 Spike protein specific immunoglobulin (Ig) G (Spike IgG) antibodies in peripheral blood samples as reported previously.(6) Serostatus was a qualitative assessment (positive or negative) based on the enzyme-linked immunoassay (ELISA) results from above.

Two study groups were defined as: seronegative and seropositive. The primary objective was to compare the univariate relationship of chronic health conditions (CHC) between seronegative versus seropositive statuses. The secondary objective was to examine the adjusted . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 associations between clinical characteristics and seronegative status. Participant characteristics are expressed as mean ± standard deviation for continuous variables, and frequency (%) for categorical variables. Relative magnitude of negative serostatus was estimated by odds ratio (OR) and 95% confidence intervals (CI).

For the secondary objective, multivariable logistic regression models were built to calculate the adjusted OR for negative serostatus in participants with CHCs or taking medications. Models were adjusted for age, sex, CHCs, and medications. P-value was considered significant at <0.05. All statistical analyses were performed using SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina).

Of the 7,046 participants enrolled from April 2021 through August 2021, a total of 1,868 were excluded from the analysis because 802 were unvaccinated, 487 were missing vaccination dates or other vaccination related critical data, 247 were missing critical demographic information or medical history, and 332 were not "Fully Vaccinated" as defined in Methods ( Figure 1 ). The final study dataset included 5,178 participants, of which, 51 were seronegative and 5,127 were seropositive. Univariate comparison of clinical characteristics between the two study groups is presented in Table 1 .

Among those with no-CHC, 22% were seronegative, whereas 42% were seropositive (OR=0.37, 95% CI: 0.19-.073; P=0.003) ( CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. 

Age > 65 years, sex, or reported history of tobacco product use were not significantly associated with seronegative status (Table 2 ). However, the presence of even one reported CHC was significantly associated with seronegative status (OR=2.69; 95%: 1.25-5.79).

Similarly, the association between pre-existing CHCs and seronegative status strengthened with an increase in the number of CHCs from two (OR=2.82; 95%: 1.14-7.0) to three or more (OR=4.52; 95%: 1.68-12.14).

In this study of 5,178 fully vaccinated participants enrolled during the beginning of the Delta variant wave, we found that those reporting no CHCs were more likely to develop detectable antibody levels (a.k.a., seropositivity) after completing vaccination regimen. Conversely, those reporting a pre-existing comorbid condition were less likely to develop a seropositive status after immunization. The highest risk of not developing a detectable antibody response was seen with CKD, although those reporting CVD, diabetes, or hypertension were also less likely to develop seropositive status after vaccination. The odds of a seronegative status increased with an increase in the number of comorbidities.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 More than 10.6 billion COVID-19 vaccine doses have been administered worldwide. (1) Although it is widely suspected that pre-existing comorbidities play a critical role in determining responses to immunization, (7) few data are available to determine the role of comorbidities on serological response or vaccine efficacy in the general public. We found that <1% of our study population failed to develop an appreciable response to the vaccine despite the high rates of diabetes (10.7%), hypertension (33.7%), and cancer (6.8%) in our cohort, which are comparable to national rates of these comorbidities. Even though serological tests do not represent the competence of an immune response, there is a significant relationship between a positive serology and SARS-CoV-2 neutralization potential, (6) suggesting that those who fail to establish a measurable seropositive status are more likely to remain vulnerable to SARS-CoV-2 infection.

Furthermore, even though a seropositive status does not guarantee successful vaccination effect (i.e., SARS-CoV-2 neutralization), a seronegative status excludes any possibility of virus neutralization. (8) About 52% adults in the United States have at least 1 CHC and about 27% have multiple CHCs. (9) According to the data presented in our study, almost half of the adult population in the United States has a two-fold chance of being vulnerable to SARS-CoV-2 (or re-infection), even if they are fully vaccinated. Although diabetes, hypertension, and CVD are well-known risk factors for severe COVID-19 outcomes,(10) our study shows that CKD is the biggest threat, even among fully vaccinated individuals as has been suspected previously. (11, 12) Our findings suggest that presence of these comorbidities significantly increases the likelihood of vaccine failure.

The Global Burden of Disease Study (GBD) has estimated one in five individuals worldwide to be at risk for severe COVID-19, primarily due to their burden of pre-existing CHCs. (11) There is a significant overlap in diseases reported by the GBD and those found to increase the likelihood of a seronegative status in our study. (13) Cancer, a major CHC in GBD, showed a very modest association with seronegative status in our study. However, current . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 treatment for cancer was strongly associated with seronegative status, indicating that treatment status might be a more accurate clinical indicator of impaired immune response rather than a clinical diagnosis of cancer. Some studies have shown a significant association between ACEi or ARB use and risk of SARS-CoV-2 infection and severity of health outcomes. (14, 15) In contrast to that, our study did not find any association, positive or negative, between ACEi or ARB use and serostatus. This suggests that use of ACEi or ARB may not affect vaccine efficacy, even if their use has the potential to influence risk of disease or its severity.

Additional work is required to elucidate whether smoking and other comorbidities influence the effectiveness of the virus neutralization capabilities post-vaccination. The results of such studies will help better shape the guidelines for booster doses and future vaccination programs.

Limitations of the study include a lack of SARS-CoV-2 titer or neutralization data, which was not the primary objective of the study, but can evaluate a continuous relationship between comorbid conditions and antibody titer and neutralization efficacy. Serological assessment is not a definitive method to measure antibody efficacy, but seropositive status has a strong correlation with virus neutralization potential. The main goal of this study was to identify differences in serostatus among fully vaccinated individuals and was not powered to study the difference between individual vaccines. Finally, this study is cross-sectional in design, which does not allow us to report change over-time.

Among fully vaccinated individuals, presence of any CHC, especially CKD or autoimmune disease, increased the likelihood of seronegative status by multi-fold. This risk increased with a concurrent increase in number of comorbidities. CHCs requiring long-term treatment, especially . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 immunosuppressants or cancer treatments, increased the likelihood of a seronegative status.

Absence of any CHC was protective and increased the likelihood of a positive serological response post-vaccination. These results will help develop appropriate guidelines for booster doses and targeted vaccination programs.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101/2022.03.15.22272432 doi: medRxiv preprint

We would like to thank all study participants who generously consented to participate in this study. We would also like to thank the City of Louisville Metro, Kentucky and various other collaborators and partners who helped us complete this important study.

All the study participants provided signed consent. This study and all the protocols were approved by the Institutional Review Board of the University of Louisville (IRB # 20.0393), which conforms to the standards currently applied in the United States. 

All authors have no financial, personal, or other conflicts of interests to disclose.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 Abbreviations: CHC -Chronic Health Conditions; CI -Confidence Interval . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org /10.1101 /10. /2022 

Who Coronavirus (Covid-19) Dashboard

Comparative Effectiveness of Moderna

Preventing Covid-19 Hospitalizations among Adults without Immunocompromising Conditions -United States

Cdc Diagnostic Tests for Covid-19

Serological Assessment of Sars-Cov-2 Infection During the First Wave of the Pandemic in

Underlying Medical Conditions and Severe Illness among 540,667 Adults Hospitalized with

Seroprevalence and Correlates of Sars-Cov-2 Neutralizing Antibodies from a Population-Based Study in Bonn

Prevalence of Multiple Chronic Conditions among Us

Meta-Analysis Investigating the Relationship between Clinical Features, Outcomes, and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2) Pneumonia

Global, Regional, and National Estimates of the Population at Increased Risk of Severe Covid-19 Due to Underlying Health Conditions in 2020: A Modelling Study

Chronic Kidney Disease Is a Key Risk Factor for Severe Covid-19: A Call to Action by the Era-Edta

Global Burden of 369 Diseases and Injuries in 204 Countries and Territories, 1990-2019: A Systematic Analysis for the Global Burden of Disease Study

Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Associated with Lower Risk of

Covid-19 in Household Contacts

International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted

Chronic Health Conditions (CHC) None, N (%)

N (%)

Autoimmune Disease, N (%)

Medications None, N (%)

N (%)

N (%)