The n e w e ng l a n d j o u r na l of m e dic i n e

Wayne D. Rosamond, Ph.D. Disclosure forms provided by the authors are available with
Anna M. Johnson, Ph.D., M.S.P.H. the full text of this letter at NEJM.org.

Jessica K. Zègre‑Hemsey, Ph.D., R.N.
University of North Carolina at Chapel Hill
Chapel Hill, NC
wayne_rosamond@​­unc​.­edu
and Others
A complete list of authors is available with the full text of this
letter at NEJM.org.
The views expressed in this letter are those of the authors and
do not necessarily represent the official views of the National
Institutes of Health.
Supported by a grant (UL1TR002489) from the National
Center for Advancing Translational Sciences, National Institutes
of Health.
1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease
and stroke statistics — 2018 update: a report from the American
Heart Association. Circulation 2018;​137(12):​e67-e492.
2. Weisfeldt ML, Everson-Stewart S, Sitlani C, et al. Ventricular
tachyarrhythmias after cardiac arrest in public versus at home.
N Engl J Med 2011;​364:​313-21.
3. Kleinman ME, Brennan EE, Goldberger ZD, et al. Part 5:
adult basic life support and cardiopulmonary resuscitation qual-
ity: 2015 American Heart Association guidelines update for car-
diopulmonary resuscitation and emergency cardiovascular care.
Circulation 2015;​132:​Suppl 2:​S414-S435.
4. Nichol G, Thomas E, Callaway CW, et al. Regional variation
in out-of-hospital cardiac arrest incidence and outcome. JAMA
2008;​300:​1423-31.
DOI: 10.1056/NEJMc1915956

Guillain–Barré Syndrome Associated with JEV Infection

To the Editor: We report data from a large
series of patients in whom the Guillain–Barré
syndrome developed after they had been infected
with Japanese encephalitis virus (JEV). JEV is a
single-stranded RNA virus that is transmitted by
mosquitoes. The first case of Japanese encepha-
litis was reported in China in 1940.1
From 2003 to 2018, a total of 51,013 cases of
Japanese encephalitis were reported in China,
with 173 cases occurring in the Ningxia province.
The largest outbreak of JEV infection in the pe-
riod from July through September 2018 occurred
in the north of Ningxia, and clusters of cases
of the Guillain–Barré syndrome were observed.
Among 289 persons with suspected cases of JEV
infection in that area, 161 patients were con-

Table 1. Clinical Findings and Laboratory Results in Patients with the Guillain–Barré Syndrome.*

Characteristic Patients (N = 47)

Median age (IQR) — yr 59 (24–63)
Male sex — no. (%) 26 (55)
JEV vaccination history — no. (%) 2 (4)
Fever — no. (%)   47 (100)
Headache — no. (%)   47 (100)
Flaccid paralysis — no. (%) 36 (77)
Areflexia or decreased reflexes — no. (%) 32 (68)
Paresthesia — no. (%) 21 (45)
Trouble breathing — no. (%) 44 (94)
Disturbance of consciousness — no. (%) 39 (83)
Median time from JEV infection to onset of Guillain–Barré syndrome 5 (3–9)
symptoms (IQR) — days†
Results of CSF analysis
Median protein level (IQR) — g/liter 0.82 (0.45–1.82)
Increased protein level — no. (%)‡ 38 (81)
Median white-cell count per mm3 (IQR) 5 (2–13)
Pathogen detection — no. (%)
JEV IgM detected in serum   47 (100)
JEV IgM detected in CSF   47 (100)
JEV strain isolated from serum 0
JEV strain isolated from CSF§ 1 (2)

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 Correspondence

Table 1. (Continued.)

Characteristic Patients (N = 47)

Antiglycolipid IgM detected by immunodot enzyme assay
In serum — no. (%) 40 (85)
Antiglycolipid IgM–positive — no./total no. (%) 12/40 (30)
Anti-GM1 IgM–positive   7/40 (18)
Anti-GM2 IgM–positive   7/40 (18)
Anti-GD1a IgM–positive 3/40 (8)
Anti-GD1b IgM–positive 3/40 (8)
In CSF — no. (%) 28 (60)
Anti-GM1 IgM–positive — no./total no. (%) 1/28 (4)
Basis for neurologic diagnosis of Guillain–Barré syndrome — no. (%)¶
Brighton criteria level 1 35 (74)
Brighton criteria level 2   8 (17)
Brighton criteria level 3 4 (9)
Diagnosis based on nerve-conduction studies and electromyography — no. (%)   47 (100)
Acute inflammatory demyelinating polyneuropathy 4 (9)
Acute motor–sensory axonal neuropathy 18 (38)
Acute motor axonal neuropathy 22 (47)
Acute sensory neuropathy 3 (6)
Treatment — no. (%)
Glucocorticoid   47 (100)
Intravenous immune globulin 28 (60)
Admission to intensive care unit 44 (94)
Mechanical ventilation 44 (94)
Follow-up after 8 mo — no. (%) 17 (36)
Limb muscle weakness — no./total no. (%) 8/17 (47)
Inability to walk — no./total no. (%) 7/17 (41)
Limb muscle atrophy — no./total no. (%) 4/17 (24)
Incontinence — no./total no. (%) 5/17 (29)
Hoarse voice — no./total no. (%) 2/17 (12)

* CSF denotes cerebrospinal fluid, IQR interquartile range, and JEV Japanese encephalitis virus.
† The onset of symptoms of the Guillain–Barré syndrome was defined as the first day of onset of limb weakness, sensory
symptoms, facial paralysis, or other neurologic symptoms.
‡ The cutoff for defining an increased CSF protein level was 0.55 g per liter.
§ One JEV strain, identified as JEV Ib, was isolated from a CSF sample obtained from one patient.
¶ Brighton criteria levels indicate the certainty of a diagnosis of the Guillain–Barré syndrome. A level 1 diagnosis is sup‑
ported by nerve-conduction studies and the presence of albuminocytologic dissociation in the CSF. A level 2 diagnosis
is supported by either a CSF white-cell count of less than 50 cells per cubic millimeter (with or without an elevated
protein level) or by results of nerve-conduction studies that are consistent with the Guillain–Barré syndrome, if the CSF
white-cell count is unavailable). A level 3 diagnosis is based on clinical features without support from nerve-conduction
or CSF studies.

firmed as having JEV infection by means of virus
isolation and immunoassay in blood and cerebro-
spinal fluid (CSF) samples; these patients under-
went electrophysiological and clinical evaluation.
Electromyographic results in 47 patients with
JEV infection were consistent with the Guillain–
Barré syndrome. Albuminocytologic dissociation
in the CSF was observed in 38 (81%) of these
patients. Diagnoses were classified as 4 cases of
acute inflammatory demyelinating polyneurop-
athy (9% of patients), 22 cases of acute motor
axonal neuropathy (47%), 18 cases of acute motor–

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 The n e w e ng l a n d j o u r na l of m e dic i n e

sensory axonal neuropathy (38%), and 3 cases of Libin Wang, Ph.D.

acute sensory neuropathy (6%) (Table 1). These
patients had had symptoms compatible with JEV
infection before the onset of the Guillain–Barré
syndrome, and they met the Brighton diagnostic
criteria for the Guillain–Barré syndrome.2
A virus strain that was isolated from a CSF
sample obtained from 1 patient was identified
by whole-gene sequencing as JEV genotype Ib.
Sural-nerve biopsies in 2 patients with acute
motor–sensory axonal neuropathy revealed axon
and myelin damage. In analyses of serum sam-
ples obtained from 40 patients, 12 (30%) had an
antiglycemic autoimmune response (mainly the
gangliosides GM1, GM2, GD1a, and GD1b), but
13 patients had received treatment with immune
globulin at least 3 days before.
A total of 28 patients (60%) had received in-
travenous immune globulin within 2 weeks after
the onset of symptoms; 15 of these patients
(54%) had clinically significant improvement in
symptoms and signs after 1 week of this treat-
ment. In July 2019, a total of 17 patients were
followed up at 8 months after discharge. Among
these patients, 47% had partial limb weakness,
23% had atrophy of limb muscles, and 29% had
incontinence (Table 1; and Table S4 and Fig. S8
in the Supplementary Appendix, available with
the full text of this letter at NEJM.org).
Although studies have reported the occur-
rence of the Guillain–Barré syndrome associ-
ated with Zika virus infection,3,4 few cases of the
Guillain–Barré syndrome after JEV infection have
been reported.5 A causal link of JEV infection
with this syndrome, as supported by the short
latency (median, 5 days) from the occurrence of
JEV infection to the development of the syn-
drome, has been observed. Therefore, this study
provides evidence of a relationship between JEV
infection and the Guillain–Barré syndrome.
Guowei Wang, M.S.
Ningxia Medical University
Yinchuan, China
Haining Li, M.D., Ph.D.
Xiaojun Yang, M.D.
Tao Guo, M.D.
Zhijun Zhao, Ph.D.
Haifeng Sun, M.D.
Xiaolin Hou, M.D.
Xiangchun Ding, M.D.
Chunyang Dou, M.D.
Qiaoli Ma, M.D.
Xiao Yang, M.D
Yanbo Wang, M.D.
General Hospital of Ningxia Medical University
Yinchuan, China
Zhao Wang, M.S.
Luxuan Wang, M.S.
Ningxia Medical University
Yinchuan, China
Jixiang Liu, M.D.
Ningxia Center for Disease Control and Prevention
Yinchuan, China
Zhenhai Wang, M.D., Ph.D.
General Hospital of Ningxia Medical University
Yinchuan, China
wangzhenhai1968@163.com
Huanyu Wang, Ph.D.
Chinese Center for Disease Control and Prevention
Beijing, China
Peng Xie, M.D.
First Affiliated Hospital of Chongqing Medical University
Chongqing, China
Ms. G. Wang and Dr. Zhenhai Wang and Drs. H. Wang and
Xie contributed equally to this letter.
Supported by grants from the Science and Technology Key
Research Program of Ningxia, China (2018BFG02017 and
2019BCG01003, to Dr. Zhenhai Wang), and the National Natural
Science Foundation of China (81960233 and 31660030, to Dr.
Zhenhai Wang).
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Wang H, Liang G. Epidemiology of Japanese encephalitis:
past, present, and future prospects. Ther Clin Risk Manag 2015;​
11:​435-48.
2. Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn
PA, Jacobs BC. Diagnosis of Guillain-Barré syndrome and valida-
tion of Brighton criteria. Brain 2014;​137:​33-43.
3. Parra B, Lizarazo J, Jiménez-Arango JA, et al. Guillain–Barré
syndrome associated with Zika virus infection in Colombia.
N Engl J Med 2016;​375:​1513-23.
4. Cao-Lormeau V-M, Blake A, Mons S, et al. Guillain-Barré
syndrome outbreak associated with Zika virus infection in
French Polynesia: a case-control study. Lancet 2016;​387:​1531-9.
5. Xiang J-Y, Zhang Y-H, Tan Z-R, Huang J, Zhao Y-W. Guillain-
Barré syndrome associated with Japanese encephalitis virus in-
fection in China. Viral Immunol 2014;​27:​418-20.
DOI: 10.1056/NEJMc1916977

A SARS-CoV-2 mRNA Vaccine — Preliminary Report

To the Editor: The positive antibody response NEJM.org)1 is a hopeful step toward controlling
to the messenger RNA (mRNA) vaccine described the Covid-19 pandemic. However, this vaccine
by Jackson et al. (published online on July 14 at and other DNA and RNA vaccines against SARS-

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