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imprints homologous or heterologous boost,
we performed temporal analysis of WA-1 andb
S-specific memory B cells (fig. S7). After the
primary vaccination series with mRNA-1273,
at week 6, the frequency of memory B cells
expressing antibody receptors dual reactive
for both WA-1 andbS was 2 to 3%, with a
much lower proportion of single WA-1- or
b-specific B cells (Fig. 4, A and B). Six months
later, at week 29, there was an ~10-fold re-
duction in the frequency of double-positive
WA-1 andbS-specific memory B cells (Fig. 4,
A and B), but these were restored (~10-fold
increase) after a boost with mRNA-1273 or
mRNA-1273.b(Fig.4).Bycontrast,boosting
did not cause an increase in the frequency
of single-positive WA-1 orbS-specific B cells
(Fig. 4). There was also expansion of a rest-

ing memory B cell population over the 6 months

after the primary mRNA-1273 vaccination se-

ries; a similar population of resting memory B

cells was present in NHPs 7 weeks after boost

(week 36) with homologous or heterologous

mRNA-1273 (Fig. 4D). This finding demonstrates

a rapid recall response of primary vaccination–

induced B cells and coincides with an increase

in neutralizing antibody responses (Fig. 1, E to

J). The NHPs that underwent primary mRNA-

1273.bvaccination had a memory B cell response

that also consisted of WA-1 andbS-specific

double-positive specificity but a higher pro-

portion of single-positivebS-specific cells (Fig.

4), consistent withb-specific skewing of anti-

body responses after mRNA-1273.bprimary

vaccination (fig. S3). These data confirm the

observation from serum antibody epitope map-

ping that both homologous and heterologous

boosting can efficiently expand memory B cell

responses that are maintained after primary

vaccination.

Vaccine boosting restimulates

mRNA-1273Ðinduced TH1 and TFH

T cell responses

mRNA-1273 has been shown to elicit CD4 re-

sponses composed of T helper 1 (TH1) and T

follicular helper (TFH) cells and a lower fre-

quency of CD8 T cells in both humans and

NHPs ( 18 , 19 , 31 ). However, the definition of

longitudinal T cell development and the po-

tential for boosting contracted memory T cells

have not yet been reported in mRNA-1273–

vaccinated NHPs. Here, consistent with prior

studies, S-specific TH1 and TFHresponses, but

SCIENCEscience.org 10 DECEMBER 2021•VOL 374 ISSUE 6573 1347

β

ββ

β

β

β

ββ

ββ

0.0

0.5

1.0

1.5

3.0

% of Memory B Cells

Memory B Cells

Week 36

β

WA-1

+

+

+

β

WA-1

ββ

ββ

A B

C

D

Fig. 4. Frequency of SARS-CoV-2 S-specific B cells in PBMCs.Rhesus
macaques (n= 8 per group) were immunized as described in fig. S1. PBMCs
were collected at weeks 6, 29, 31, and 36 and analyzed by flow cytometry.
(A) Representative flow cytometry plots from one NHP per vaccine group
depicting the frequency of memory B cells that bind the WA-1 S and/orbS,
at various time points after vaccination. (B) Pie charts representing the fraction
of S-specific B cells that are single positive for the WA-1 (white,b-WA-1+),
double positive for WA-1 andb(gray,b+WA-1+), and single positive forb

(black, b+WA-1–) for all NHPs in each group. (C) Frequency ofb-WA-1+,b+WA-1+,

andb+WA-1–memory B cells at week 36 in each of the vaccine groups. Boxes

and horizontal bars denote the IQRs and medians, respectively; whisker end

points are equal to the maximum and minimum values. Circles represent

individual NHPs. (D) Pie charts representing the fraction of S-specific B cells that

are naïve (white, CD21+/CD27–), tissue-like memory (gray, CD21–/CD27–),

activated memory (black, CD21–/CD27+), and resting memory (black and white,

CD21+/CD27+) for all NHPs in each group.

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