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Center, Seattle, WA, USA. 3Department of Biostatistics, University of Washington, Seattle, WA, USA. 4Department of Surgery and Duke Human Vaccine Institute, Duke
University Medical Center, Durham, NC, USA. 5Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD,
USA. 6Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA. 7Moderna, Inc., Cambridge, MA, USA.
8Biomedical Advanced Research and Development Authority, Washington, DC, USA. 9Division of Biostatistics, School of Public Health, University of California Berkeley,
Berkeley, CA, USA. 10Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. 11Brigham and Women’s Hospital, Boston, MA, USA.
12Palm Beach Research Center, West Palm Beach, FL, USA. 13Keystone Vitalink Research, Greenville, SC, USA. 14Department of Medicine, Division of Infectious Diseases,
UNC HIV Cure Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. 15Division of Infectious Diseases, Department of Medicine,
Vanderbilt University Medical Center, Nashville, TN, USA. 16Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine and the Grady
Health System, Atlanta, GA, USA. 17Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. 18Center for Vaccine Development and
Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. 19Biostatistics Research Branch National Institute of Allergy and Infectious Diseases, National
In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing
and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These
immune markers were measured at second vaccination and 4 weeks later, with values reported in
standardized WHO International Units. All markers were inversely associated with COVID-19 risk and
directly associated with vaccine efficacy. Vaccine recipients with post-vaccination 50% neutralization
titers 10, 100, and 1000 had estimated vaccine efficacy of 78% (95% confidence interval 54, 89%), 91%
(87, 94%), and 96% (94, 98%), respectively. These results help define immune marker correlates of
protection and may guide approval decisions for mRNA COVID-19 vaccines and other COVID-19 vaccines.
Based on their demonstrated efficacy to prevent coronavirus more transmissible viral variants, highlight the need for a
disease 2019 (COVID-19) in phase 3 clinical trials, to date large armamentarium of safe and effective COVID-19
seven COVID-19 vaccines have been granted an Emergency vaccines (4, 5).
Use Listing by the World Health Organization (WHO) (1), The Coronavirus Efficacy (COVE) phase 3 trial
three have been granted an Emergency Use Authorization (NCT04470427) of the mRNA-1273 COVID-19 vaccine, which
(EUA) by the US Food and Drug Administration (FDA) (2), is being conducted in the United States in adults aged 18 and
and one has been formally approved by the FDA (3). over, showed estimated vaccine efficacy against COVID-19 of
However, the manufacturing challenges posed by the global 94% in the primary analysis (6). These efficacy data sup-
demand for doses, the need for affordable and accessible ported the US Food and Drug Administration’s EUA of
options that are safe and effective in diverse populations, the mRNA-1273 for prevention of COVID-19 in adults (7). The
current lack of efficacy data in certain populations (e.g., mRNA-1273 vaccine has been shown to be highly effective in
pediatrics, pregnant women, autoimmune or the elderly and in essential and frontline workers, including
immunocompromised individuals), and the emergence of healthcare workers (8), and to have non-inferior binding and
First release: 23 November 2021 science.org (Page numbers not final at time of first release) 1
neutralizing antibody responses in adolescents vs. adults (9). future analyses of how the current level of antibody correlates
Correlates of protection, which are immunological mark- with instantaneous risk of COVID-19. Such analyses may in-
ers that can be used to reliably predict the level of vaccine form how vaccine efficacy wanes as antibody levels wane and
efficacy against a clinically relevant endpoint such as COVID- as new variants emerge, which in turn may inform decisions
19 (10–12), are highly sought in vaccine research. The identi- about the timing of a potential third dose of vaccination
fication and validation of a correlate of protection would ex- and/or the need to update vaccine composition (26).
pedite the clinical evaluation and regulatory approval process
for existing vaccines for new populations, for vaccine regimen Antibody marker levels are lower in vaccine recipient
modifications, and for new vaccines. Neutralizing antibodies cases versus non-cases
(nAbs) or binding antibodies (bAbs) have been established as At Day 57, almost 100% of vaccine recipients had positive/de-
a correlate of protection for vaccines against many viral dis- tectable antibody response by all four markers (Table 1; table
eases (11). The hypothesis that antibodies, whether elicited by S3 shows assay limits for each marker). This was also true at
infection or by spike protein-based vaccines, are a correlate Day 29 for spike IgG and RBD IgG, whereas ID50 and ID80
of protection against COVID-19 is supported by diverse lines titers were detectable in 82% and 64% of vaccine recipients,
of evidence (13–25). For the mRNA-1273 vaccine, multiple se- respectively. Each marker was moderately correlated be-
vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tween the Day 29 and Day 57 time points (Spearman rank r
antibody markers including IgG bAbs to the spike protein, = 0.53 to 0.62; fig. S4). Together the spike IgG and RBD IgG
IgG bAbs to spike receptor binding domain (RBD), and 50% markers were tightly correlated (Spearman rank r = 0.94, 0.97
(ID50) inhibitory dilution nAb titer, each correlated with pro- at Day 29, 57; figs. S5 and S6), as were the ID50 and ID80
tection against SARS-CoV-2 replication after challenge in vac- markers (r = 0.97, 0.96 at Day 29, 57; figs. S5 and S6). Accord-
cinated rhesus macaques (24). Here we assessed these same ingly, some results focus on spike IgG and ID50. Each binding
SARS-CoV-2 antibody markers, and in addition, 80% inhibi- antibody marker was correlated with each neutralization
tory dilution (ID80) nAb titer, as correlates of risk of COVID- marker at each time point (r = 0.73 to 0.80).
19 and as correlates of mRNA-1273 vaccine protection against Figure 1 and fig. S7 show the Day 29 and Day 57 marker
COVID-19 in the COVE trial. distributions by case/non-case status in vaccine recipients
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were obtained across pre-specified vaccine recipient sub- = 22% vs. 4%). Vaccine efficacy estimates also increased with
groups (Fig. 3, B and C, and fig. S17). Day 29 ID50 neutralization titers: 79% (−62, 90%), 93% (90,
The four markers at Day 29 were also significant inverse 95%), 97% (95, 99%), and 99 (97, 100%) at the same IU50/ml
correlates of risk, with estimated hazard ratios for upper vs. values (fig. S22).
lower tertiles ranging between 0.19 and 0.32 (figs. S18 and Figures S23 to S28 show these results for the other six an-
S19), and estimated hazard ratios per 10-fold increase in tibody markers. Conclusions for binding antibodies were sim-
marker value ranging between 0.19 and 0.54 (fig. S17). P-val- ilar to those for neutralizing antibodies, with vaccine efficacy
ues were smaller for Day 29 than Day 57 markers indicating increasing with IgG levels, for example at Day 57 spike IgG of
strengthened evidence for correlates of risk. If a Day 29 im- 33, 300, and 4000 BAU/ml, vaccine efficacy was 85% (31,
mune marker in recipients of two mRNA-1273 doses becomes 92%), 90% (77, 94%), and 94% (91, 96%), respectively. An-
established as a correlate of protection, it could be a more other conclusion of these analyses is that subgroups with
practical surrogate marker than a Day 57 marker. Of note, all neutralization titer 10 IU50/ml (Fig. 4C) or with anti-spike
participants in our correlates analysis received both dose 1 IgG 33 BAU/ml (fig. S24C) have about 75-85% reduction in
and dose 2, and thus the Day 29 correlates results reflect the COVID-19 risk compared to being unvaccinated. Given the
full effect of the two vaccine doses used in clinical practice. overall similarity of the binding antibody and neutralizing
The estimated cumulative incidence of COVID-19 by end antibody correlate of protection results, the potential value of
of blinded follow-up (100 days post Day 57) for the entire vac- the validated MSD binding antibody assay for aiding vaccine
cine group was 0.0033 (95% CI 0.0022, 0.0045). Based on approval decisions as a practical non-mechanistic CoP (12)
nonparametric threshold regression this cumulative inci- should be considered. This is because the MSD binding anti-
dence decreased across vaccinated subgroups with Day 57 body assay is sensitive (table S3), robust, high-throughput,
ID50 titer above a given threshold, with zero COVID-19 end- deployable and easily standardized across viral strains, even
points at ID50 titer above 1000 IU50/ml (Fig. 4A). The shape though validated sensitive binding antibody detection may
of cumulative incidence across threshold subgroups tracked lack the specific immune function such as neutralization.
the reverse cumulative distribution function of ID50 titer,
suggesting a smooth incremental change in risk with titer A sensitivity analysis further increases confidence that
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57 antibody marker could be highly effective in guiding indi- against virologically confirmed influenza B/Victoria illness
vidual decisions of whether to be re-vaccinated or boosted. (31). As hemagglutination inhibition titer has been used to
Yet, if a vaccinated person has negative IgG response or un- guide influenza vaccine strain selection and approval, this de-
detectable neutralization response, based on our results it fines a potential benchmark for influencing COVID-19 vac-
would be rational for this person to be concerned about rela- cine approval decisions (32).
tively weak protection and hence prompting seeking out A possible interpretation also consistent with our results
other means of protection. is that neutralization as a biological function mediated a
large proportion of the vaccine efficacy, but the specific Day
Neutralizing antibodies mediate about two-thirds of the 29 ID50 and ID80 immune markers studied, measured with
mRNA-1273 vaccine efficacy a particular immunoassay, had inadequate sensitivity to
For binding antibodies at both time points, and for neutral- quantify low-level neutralization below the positivity cutoff
izing antibodies at Day 57, a challenging issue is understand- that could be present and functionally important. Passive
ing vaccine efficacy for vaccine recipients with transfer of purified IgG from mRNA-1273-immunized rhesus
negative/undetectable antibody level, given that fewer than macaques protected golden Syrian hamsters from disease af-
2% of vaccine recipients had negative or undetectable anti- ter SARS-CoV-2 challenge, suggesting functionally active an-
bodies. Consequently, the 95% confidence intervals about tibodies can mediate protection (24). However, additional
vaccine efficacy for these subgroups were wide and assess- immune markers are likely needed to fully explain the ob-
ment of mediation through these markers was not technically served vaccine efficacy in COVE, for example markers meas-
possible because of insufficient overlap of marker values in uring additional immune functions beyond neutralization
placebo and vaccine recipients. However, Day 29 ID50 and (e.g., Fc effector functions or functional T cells), markers not
ID80 titers could be assessed as mediators of vaccine efficacy measured fully in serum (e.g., mucosal), and/or anamnestic
by the Benkeser et al. method (30), given that 18% and 36% responses not fully represented by a single time point meas-
of vaccine recipients had undetectable titer, respectively, urement.
providing enhanced precision [e.g., estimated vaccine effi- Further clarification of functional mediation of protection
cacy 79% (95% CI 62, 90%) at undetectable ID50]. The quan- may be provided by future correlates analyses that study an-
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IgG levels of 113 (95% CI < LOD = 0.31, 245) and 899 (369, model where COVID-19 risk decreased incrementally with in-
NC) BAU/ml, respectively, and at RBD IgG levels of 165 (< creasing increments in antibody level, rather than a thresh-
LOD = 1.59, 452) and 2360 (723, NC) BAU/ml, respectively old model where an antibody cut-point sharply discriminated
(NC = not calculated) (19). For COVE, there is low precision risk.
at 70% vaccine efficacy because few vaccine recipients had Together with evidence from other studies, the current re-
IgG < 100 BAU/ml, such that we only compare results at 90% sults support that neutralization titer is a potential surrogate
vaccine efficacy. Estimated mRNA-1273 vaccine efficacy was marker for mRNA-1273 vaccination against COVID-19 that
90% at Day 57 spike IgG level 298 (1, 1786) BAU/ml and at can be considered as a primary endpoint for basing certain
Day 57 RBD IgG level of 775 (29, 2819) BAU/ml. While the provisional approval decisions. For example, an immunogen-
point estimates of IgG levels at 90% efficacy were about 3 icity non-inferiority approach has been proposed for adding
times higher for COV002 than for COVE, the overlapping con- vaccine spike variants and boosters (34). An advantage of a
fidence intervals are consistent with similar results across the non-inferiority approach is avoiding the need to specify an
two trials. absolute antibody benchmark for approval, such as based on
Pseudovirus neutralization results can also be compared percentage of vaccine recipients with ID50 titer above a
between the trials using ID50 titers calibrated to the Interna- threshold and geometric mean titer above a threshold. Yet,
tional Standard, where estimated AZD1222 vaccine efficacy some applications may be aided by an absolute benchmark if
was 70% and 90% at ID50 titer of 8 (< LOD = 2.42, 26) and data allowing head-to-head non-inferiority evaluation are un-
140 (43, NC) IU50/ml, compared to COVE results at ID50 titer available. Such a benchmark based on ID50 values from vac-
of 4 (< LOD = 2.42, 22) and 83 (16, 188) IU50/ml. These results cinated individuals in a bridging study could be based on
support that neutralizing antibody titers have a similar quan- predicted vaccine efficacy being sufficiently high, where, for
titative relationship with vaccine efficacy for the two vaccine example, predicted vaccine efficacy could be calculated based
platforms, which is promising for potential applications of a on the COVE correlates of protection results (e.g., Fig. 4C) and
neutralization biomarker. The materials and methods pro- averaging over the distribution of ID50 values.
vide a sensitivity analysis comparing correlate of protection The evidence level for justifying various bridging applica-
results between COV002 and COVE. tions differs across applications, where currently confidence
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48. B. D. Williamson, P. B. Gilbert, N. R. Simon, M. Carone, A general framework for and Gilead, as well as payments from Medscape and from Clinical Care Options
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50. S. D. Neidich, Y. Fong, S. S. Li, D. E. Geraghty, B. D. Williamson, W. C. Young, D. influenza vaccine research; and DCM declares support from Moderna within the
Goodman, K. E. Seaton, X. Shen, S. Sawant, L. Zhang, A. C. deCamp, B. S. Blette, previous three years for work outside the scope of the submitted work. All other
M. Shao, N. L. Yates, F. Feely, C.-W. Pyo, G. Ferrari, HVTN 505 Team, I. Frank, S. authors declare no support from any organization for the submitted work; no
T. Karuna, E. M. Swann, J. R. Mascola, B. S. Graham, S. M. Hammer, M. E. financial relationships with any organizations that might have an interest in the
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1 risk. J. Clin. Invest. 129, 4838–4849 (2019). doi:10.1172/JCI126391 Medline materials availability: As the trial is ongoing, access to participant-level data
51. C. A. Magaret, D. C. Benkeser, B. D. Williamson, B. R. Borate, L. N. Carpp, I. S. and supporting clinical documents with qualified external researchers may be
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Edugupanti, P. B. Gilbert, Prediction of VRC01 neutralization sensitivity by HIV-1 Commons Attribution 4.0 International (CC BY 4.0) license, which permits
gp160 sequence features. PLOS Comput. Biol. 15, e1006952 (2019). unrestricted use, distribution, and reproduction in any medium, provided the
doi:10.1371/journal.pcbi.1006952 Medline original work is properly cited. To view a copy of this license, visit
52. B. D. Williamson, J. Feng, N. Simon, M. Carone, vimp: Perform Inference on https://creativecommons.org/licenses/by/4.0/. This license does not apply to
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Fig. 1. (A) Anti-spike IgG concentration and (B) pseudovirus neutralization ID50 titer by COVID-19 outcome
status. Data points are from baseline negative per-protocol vaccine recipients in the Day 29 marker or Day 57
marker case-cohort set. The violin plots contain interior box plots with upper and lower horizontal edges the 25th
and 75th percentiles of antibody level and middle line the 50th percentile, and vertical bars the distance from the
25th (or 75th) percentile of antibody level and the minimum (or maximum) antibody level within the 25th (or 75th)
percentile of antibody level minus (or plus) 1.5 times the interquartile range. Each side shows a rotated
probability density (estimated by a kernel density estimator with a default Gaussian kernel) of the data. Positive
response rates were computed with inverse probability of sampling weighting. Pos.Cut, Positivity cut-off. LoD,
limit of detection. ULoQ, upper limit of quantitation; ULOQ = 10,919 for ID50 (above all data points). Positive
response for spike IgG was defined by IgG > 10.8424 BAU/ml. Positive response for ID50 was defined by value
> LoD (2.42). Post Day 57 cases are COVID-19 endpoints starting 7 days post Day 57 through the end of blinded
follow-up (last COVID-19 endpoint 126 days post dose 2); Intercurrent cases are COVID-19 endpoints starting 7
days post Day 29 through 6 days post Day 57.
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Fig. 2. COVID-19 risk by antibody marker level. The plots and table show covariate-adjusted cumulative
incidence of COVID-19 by Low, Medium, High tertile of Day 57 IgG concentration or pseudovirus
neutralization titer in baseline SARS-CoV-2 negative per-protocol participants. (A) Anti-spike IgG
concentration; (B) ID50 titer; (C) IgG (spike, RBD) and (ID50, ID80). The overall p-value is from a
generalized Wald test of whether the hazard rate of COVID-19 differed across the Low, Medium, and High
subgroups. Baseline covariates adjusted for: baseline risk score, at risk status, community of color status.
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Fig. 3. Hazard ratio of COVID-19 as antibody marker level increases. The table and plots show
covariate-adjusted hazard ratios of COVID-19 per 10-fold increase in each Day 57 antibody marker
in baseline negative per-protocol vaccine recipients overall and in subgroups. (A) Inferences for
IgG (spike, RBD) and (ID50, ID80); (B) Forest plots for spike IgG; (C) Forest plots for ID50.
Baseline covariates adjusted for: baseline risk score, at risk status, community of color status.
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Fig. 4. Further analyses of Day 57 ID50 level as a correlate of risk and as a correlate of protection. (A)
Covariate-adjusted cumulative incidence of COVID-19 by 100 days post Day 57 by vaccinated baseline SARS-
CoV-2 negative per-protocol subgroups defined by Day 57 ID50 level above a threshold, with reverse cumulative
distribution function (CDF) of Day 57 ID50 level overlaid in green. The red dots are point estimates at 35
threshold values equally spaced over quantiles of the observed marker values, linearly interpolated by solid black
lines; the gray shaded area is pointwise 95% confidence intervals (CIs). The upper boundary of the green shaded
area is the estimate of the reverse cumulative distribution function (CDF) of Day 57 ID50 level in baseline SARS-
CoV-2 negative per-protocol vaccine recipients. The vertical red dashed line is the Day 57 ID50 threshold above
which no post Day 57 COVID endpoints occurred. (B) Covariate-adjusted cumulative incidence of COVID-19 by
100 days post Day 57 by Day 57 ID50 level. The dotted black lines indicate bootstrap point-wise 95% CIs. The
upper and lower horizontal gray lines are the overall cumulative incidence of COVID-19 from 7 to 100 days post
Day 57 in placebo and vaccine recipients, respectively. (C) Vaccine efficacy (solid black line) by Day 57 ID50
level, estimated using the method of Gilbert, Fong, and Carone (28). The dashed black lines indicate bootstrap
point-wise 95% CIs. The horizontal gray line is the overall vaccine efficacy from 7 to 100 days post Day 57, with
the dotted gray lines indicating the 95% CIs (this number 92.8% differs from the 94.1% reported in (6), which
was based on counting COVID-19 endpoints starting 14 days post Day 29). In (B) and (C), the green histograms
are an estimate of the density of Day 57 ID50 level in baseline negative per-protocol vaccine recipients. LOD, limit
of detection. Baseline covariates adjusted for: baseline risk score, at risk status, community of color status.
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Table 1. Anti-spike and anti-RBD IgG response rates and Geometric Mean Concentrations (GMCs) and pseudovirus calibrated neutraliza-
tion titer ID50 and ID80 response rates and Geometric Mean Titers (GMTs) by COVID-19 outcome status. Analysis based on baseline nega-
tive per-protocol vaccine recipients in the Day 29 marker or Day 57 marker case-cohort sets. Median (interquartile range) days from dose one to
Day 29 was 28 (28 to 30) and from Day 29 to Day 57 was 28 (28 to 30).
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Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial
Peter B. GilbertDavid C. MontefioriAdrian B. McDermottYouyi FongDavid BenkeserWeiping DengHonghong ZhouChristopher R.
HouchensKaren MartinsLakshmi JayashankarFlora CastellinoBritta FlachBob C. LinSarah O’ConnellCharlene McDanalAmanda
EatonMarcella Sarzotti-KelsoeYiwen LuChenchen YuBhavesh BorateLars W. P. van der LaanNima S. HejaziChuong
HuynhJacqueline MillerHana M. El SahlyLindsey R. BadenMira BaronLuis De La CruzCynthia GaySpyros KalamsColleen
F. KelleyMichele P. AndrasikJames G. KublinLawrence CoreyKathleen M. NeuzilLindsay N. CarppRolando PajonDean
FollmannRuben O. DonisRichard A. Koup, and Oleg Borisov, and Brett Chromy, and Mark Delvecchio, and Tremel Faison,
and Corey Hoffman, and Tom Hu, and Pennie Hylton, and Aparna Kolhekar, and James Little, and Jeanne Novak, and Carol
Sabourin, and Evan Sturtevant, and Xiaomi Tong, and John Treanor, and Danielle Turley, and Leah Watson, and Gian King,
and Andrew Li, and Najaf Shah, and Smruthi Suryaprakash, and Jue Xiang Wang, and Patricia D’Souza, and Janie Russell,
and David Beaumont, and Kendall Bradley, and Jiayu Chen, and Xiaoju Daniell, and Thomas Denny, and Elizabeth Domin, and
Kelsey Engel, and Wenhong Feng, and Juanfei Gao, and Hongmei Gao, and Kelli Greene, and Sarah Hiles, and Leihua Liu,
and Kristy Long, and Kellen Lund, and Francesca Suman, and Haili Tang, and Jin Tong, and Olivia Widman, and Christopher
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and Mursal Naisan, and Muhammed Naqvi, and Sandeep Narpala, and Abhinaya Srikanth, and Clare Whittaker, and Weiwei
Wu, and Shu Hahn, and Di Lu, and James Zhou, and Jessica Andriesen, and Andrew Fiore-Gartland, and Ying Huang, and
Yunda Huang, and Ellis Hughes, and Ollivier Hyrien, and Holly E. Janes, and Michal Juraska, and April K. Randhawa, and
Brian Simpkins, and Brian D. Williamson, and Michael P. Fay, and Martha Nason, and Marco Carone, and Kendrick Li, and
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Steven Shinn, and Marshall Nash, and Sinikka L. Green, and Colleen Jacobsen, and Jayasree Krishnankutty, and Sikhongi
Phungwayo, and Richard M. Glover II, and Stacy Slechta, and Troy Holdeman, and Robyn Hartvickson, and Amber Grant, and
Terry L. Poling, and Terry D. Klein, and Thomas C. Klein, and Tracy R. Klein, and William B. Smith, and Richard L. Gibson, and
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