vaccine compared with a group of SARS-
CoV-2–recovered vaccinees generating recall
responses from preexisting immunity. These
analyses provide insights into mRNA vaccine–
induced immunological memory and may be
relevant for future vaccine strategies, includ-
ing recommendations for additional booster
vaccine doses.
Results and discussion
Cohort design
We collected 348 longitudinal samples from
61 individuals receiving either the Pfizer
BNT162b2 (N= 54) or Moderna mRNA-1273
(N= 7) SARS-CoV-2 vaccines at six time points
(Fig. 1A), ranging from prevaccination base-
line to 6 months postvaccination. This study
design allowed us to monitor the induction
and maintenance of antigen-specific immune
responses to the vaccine. Specifically, sampling
at 1, 3, and 6 months postvaccination enabled
the analysis of immune trajectories from peak
responses after the second vaccine dose through
the establishment and maintenance of immu-
nological memory. This cohort was divided into
two groups on the basis of prior SARS-CoV-2
infection (N= 45 SARS-CoV-2–naïve individu-
als;N= 16 SARS-CoV-2–recovered individuals).
Ageandsexwerebalancedinbothgroups.
Paired serum and peripheral blood mono-
nuclear cell (PBMC) samples were collected
from all individuals, allowing for a detailed
analysis of both serologic and cellular immune
memory to SARS-CoV-2 antigens. Notably, the
subjects with a prior infection allowed us to
study the dynamics of reactivating preexisting
immunity with mRNA vaccines. Though pre-
existing immunity generated by infection may
differ from that generated by vaccination, re-
sponses observed in this group may provide
insights into the boosting of vaccine-induced
immunity using additional doses of vaccine.
Antibody responses to SARS-CoV-2
mRNA vaccines
We first measured anti-spike and anti-RBD
binding antibody responses in plasma sam-
ples by enzyme-linked immunosorbent assay
(ELISA). As reported previously by our group
and others, mRNA vaccines induced robust
circulating antibody responses to the SARS-
CoV-2 spike protein and spike RBD with distinct
patterns of early response in SARS-CoV-2–naïve
and–recovered individuals (Fig. 1B) ( 16 , 34 – 36 ).
Goelet al.,Science 374 , eabm0829 (2021) 3 December 2021 2of17
(^131030131030131030)
10
30
100
300
anti−Spike IgG
FRNT50
(^131013101310)
10
30
100
300
anti−RBD IgG
FRNT50
p = 4.3e-08
p = 3.9e-07
p = 1.7e-04
p = 1.8e-04
= 0.8 = 0.62 = 0.81
p = 2.4e-08
= 0.76 = 0.62 = 0.83
p = 1e-08
E
Naive Recovered
D614GB.1.351B.1.617
.2
D614
G
B.^1 .351B.1.^6 17.2
10
100
1000
10000
FRNT50
6 Months
0.052
ns
10
100
1000
10000
(^050100150200)
Days Post−Vaccine
FRNT50
D614G Neutralization
10
100
1000
10000
0 2 4 6
Months
D614G
10
100
1000
10000
(^050100150200)
Days Post−Vaccine
FRNT50
B.1.351 Neutralization
10
100
1000
10000
0 2 4 6
Months
B.1.351
44/4516/16 33/339/9
43/45
16/16
31/33
9/9
t1/2 = 51d t1/2 = 72d
t1/2 = 45d
t1/2 = 49d
t1/2 = 63d
t1/2 = 231d
p = 0.17
Decay Rates = ns
Decay Rates = signif
p = 6.2x10-5
SARS-CoV-2 Naive
N = 45
SARS-CoV-2 Recovered
N = 16
- mRNA
Vaccine
Age: 36.9 [22-67]
Sex: 21M 24F
Age: 38.3 [23-59]
Sex: 10M 6F
A
1
10
100
1000
(^050100150200)
Days Post−Vaccine
ug/mL
anti−Spike IgG
1
10
100
1000
0 2 4 6
Months
anti−Spike IgG
1
10
100
1000
(^050100150200)
Days Post−Vaccine
ug/mL
anti−RBD IgG
1
10
100
1000
0 2 4 6
Months
anti−RBD IgG
B
C
Dose 1 +2wks Dose 2
T1 T2 T3 T4
+1wk
T5 T6
3 months 6 months
Memory
Cellular Memory
D
4 8 4 8
Serology
45/45
16/16
32/32
9/9
45/45
16/16
31/32
9/9
p = 0.11
Decay Rates = ns
Decay Rates = signif
p = 3.5x10-4
BB
Mean: 136 80 117 15954331372
D614G B.1.351 B.1.617.2
Pfizer
Moderna
Variant:
t1/2 = 47d
t1/2 = 28d
t1/2 = 47d
t1/2 = 42d
t1/2 = 33d t1/2 = 48d
Fig. 1. SARS-CoV-2 mRNA vaccines induce robust antibody responses.
(A) University of Pennsylvania COVID-19 vaccine study design and cohort
summary statistics. (B) Anti-spike and anti-RBD IgG concentrations over time in
plasma samples from vaccinated individuals. (C) Pseudovirus neutralization
titers against WT D614G or B.1.351 variant spike protein over time in plasma
samples from vaccinated individuals. Data are represented as focus reduction
neutralization titer 50% (FRNT 50 ) values. (D) Comparison of D614G, B.1.351, and
B.1.617.2 FRNT 50 values at 6 months postvaccination. (E) Correlation between
anti-spike or anti-RBD IgG and neutralizing titers (D614G = black, B.1.351 = green,
and B.1.617.2 = orange; statistics were calculated using nonparametric Spearman
rank correlation). Dotted lines indicate the limit of detection for the assay.
For (B) and (C), black triangles indicate time of vaccine doses, fractions above
plots indicate the number of individuals above their individual baseline at
memory time points, and summary plots show mean values with the 95%
confidence interval. Decay rates were calculated using a piecewise linear mixed-
effects model with censoring. Changes in decay rate over time (linear versus
two-phase decay) were determined on the basis of a likelihood ratio test.DDecay
Rates indicates whether decay rates were different in SARS-CoV-2–naïve
and–recovered groups. Statistics were calculated using unpaired [(B) and (C)]
or paired (D) nonparametric Wilcoxon test with Benjamini-Hochberg (BH)
correction. Blue and red values indicate comparisons within naïve or recovered
groups. P< 0.05; P< 0.01; P< 0.001; ****P< 0.0001; ns, not significant.
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