One of the key questions in predicting the course of the COVID-19 pandemic, caused
by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is how well and how
long the immune responses protect the host from reinfection. For some viruses, the
first infection can provide lifelong immunity; for seasonal coronaviruses, protective
immunity is short-lived.
1
In The Lancet Infectious Diseases, Richard L Tillett and colleagues describe the first
confirmed case of SARS-CoV-2 reinfection in the USA.
2
A 25-year-old man from the US state of Nevada, who had no known immune disorders,
had PCR-confirmed SARS-CoV-2 infection in April, 2020 (cycle threshold [Ct] value
35·24; specimen A). He recovered in quarantine, testing negative by RT-PCR at two
consecutive timepoints thereafter. However, 48 days after the initial test, the patient
tested positive again by RT-PCR (Ct value 35·31; specimen B). Viral genome sequencing
showed that both specimens A and B belonged to clade 20C, a predominant clade seen
in northern Nevada. However, the genome sequences of isolates from the first infection
(specimen A) and reinfection (specimen B) differed significantly, making the chance
of the virus being from the same infection small. What is worrisome is that SARS-CoV-2
reinfection resulted in worse disease than did the first infection, requiring oxygen
support and hospitalisation. The patient had positive antibodies after the reinfection,
but whether he had pre-existing antibody after the first infection is unknown (table
).
Table
Characteristics associated with reinfection with SARS-CoV-2
Sex
Age (years)
First infection (Ct)
Second infection (Ct)
Intervening period (days)
Antibody after first infection
Antibody after reinfection
Hong Kong
3
Male
33
Mild (N/A)
Asymptomatic (27)
142
Negative
IgG+
Nevada, USA
2
Male
25
Mild (35)
Hospitalised (35)
48
N/A
IgM+ and IgG+
Belgium
4
Female
51
Mild (26–27)
Milder (33)
93
N/A
IgG+
Ecuador
5
Male
46
Mild (37)
Worse (N/A)
63
IgM– and IgG–
IgM+ and IgG+
Data were obtained Sept 14, 2020, for reinfection cases confirmed by viral genome
sequences. Ct=cycle threshold. N/A=not available. SARS-CoV-2=severe acute respiratory
syndrome coronavirus 2.
This case report adds to rapidly growing evidence of COVID-19 reinfection, in which
viral genomic sequences were used to confirm infections by distinct isolates of SARS-CoV-2.
What do reinfection cases mean for public health and vaccination endeavors to stop
the COVID-19 pandemic?
Do reinfections occur because of a scant antibody response after first infection?
Of the four reinfection cases reported to date, none of the individuals had known
immune deficiencies. Currently, only two individuals had serological data from the
first infection and one had pre-existing antibody (IgM) against SARS-CoV-2. Because
of the wide range of serological testing platforms used across the globe, it is impossible
to compare results from one assay to another. For example, antibody reactivity to
nucleocapsid protein indicates previous exposure to SARS-CoV-2 but not whether antibodies
that can block infection (anti-spike) are present. Also, antibody levels are highly
dependent on the timing after exposure. The key goal for the future is to ascertain
the level and specificity of antibody to spike protein at the time of reinfection,
to determine immune correlate of protection.
Does immunity protect an individual from disease on reinfection? The answer is not
necessarily, because patients from Nevada and Ecuador had worse disease outcomes at
reinfection than at first infection. It is important to keep in mind that the reinfection
cases in general are being picked up because of symptoms and are biased towards detection
of symptomatic cases. Due to the paucity of broad testing and surveillance, we do
not know how frequently reinfection occurs among individuals who recovered from their
first infection. Asymptomatic reinfection cases can only be picked up by routine community
testing or at an airport, for example,
3
and we are probably severely underestimating the number of asymptomatic reinfections.
Why do some reinfections result in milder disease,3, 4 whereas others are more severe?2,
5 Further investigation is needed of pre-existing immune responses before second exposure,
and viral inoculum load.
Does infection by different viral isolates mean we need a vaccine for each type? While
differences in the viral genome sequence of the various isolates are a great way to
know if an individual is reinfected (ruling out reactivation of lingering virus infection),
it does not indicate that the second infection was due to immune evasion. There is
currently no evidence that a SARS-CoV-2 variant has emerged as a result of immune
evasion. For now, one vaccine will be sufficient to confer protection against all
circulating variants.
6
Furthermore, reinfection by a distinct viral variant from the original virus does
not imply immune escape.
Does immunity prevent transmission from those who are reinfected? The Ct value of
PCR correlates with viral load, and low Ct values (high viral load) might indicate
infectiousness of the individual. Although Ct values can vary substantially between
various tests and laboratories, in one study, samples with Ct values greater than
35 were only 8% positive for cultivable virus.
7
A good proxy for infectiousness can be obtained through viral plaque assays that measure
the infectious virus. However, these assays require biosafety level 3 facilities and
are labour intensive, and the assays are not routinely done in clinical laboratories.
Since some reinfection cases had Ct values less than 35,3, 4 infectious virus might
have been harboured in the nasal cavity. Thus, reinfection cases tell us that we cannot
rely on immunity acquired by natural infection to confer herd immunity; not only is
this strategy lethal for many but also it is not effective. Herd immunity requires
safe and effective vaccines and robust vaccination implementation.
As more cases of reinfection surface, the scientific community will have the opportunity
to understand better the correlates of protection and how frequently natural infections
with SARS-CoV-2 induce that level of immunity. This information is key to understanding
which vaccines are capable of crossing that threshold to confer individual and herd
immunity.
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2020
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