Comment

induced SARS-CoV-2 antibodies after vaccination with 1 Tregoning JS, Brown ES, Cheeseman HM, et al. Vaccines for COVID-19.
Clin Exp Immunol 2020; published online Sept 15. https://doi.org/10.1111/
inactivated SARS-CoV-2 vaccines is critically important. cei.13517.
In addition, more studies are needed to establish 2 Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against
SARS-CoV-2 - Preliminary Report. N Engl J Med 2020; published online
whether the inactivated SARS-CoV-2 vaccines are July 14. https://doi.org/10.1056/NEJMoa2022483.
capable of inducing and maintaining virus-specific T-cell 3 Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant
adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged
responses, because CD4-positive T-cell help is important 18 years or older: a randomised, double-blind, placebo-controlled,
phase 2 trial. Lancet 2020; 396: 479–88.
for optimal antibody responses, as well as for cytotoxic 4 Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the
CD8-positive T-cell activation, which, in turn, are crucial ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a
phase 1/2, single-blind, randomised controlled trial. Lancet 2020; 396: 467–78.
for viral clearance if neutralising antibody-mediated 5 Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity
protection is incomplete.10 of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19
vaccine in two formulations: two open, non-randomised phase 1/2 studies
Finally, because the correlates of protection afforded from Russia. Lancet 2020; 396: 887–97.
by inactivated SARS-CoV-2 vaccines are yet to be 6 Xia S, Duan K, Zhang Y, et al. Effect of an inactivated vaccine against
SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of
identified, the results of a phase 3 trial of BBIBP-CorV 2 randomized clinical trials. JAMA 2020; 324: 1–10.
7 Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an
vaccine (currently underway in Abu Dhabi, United Arab inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind,
Emirates; ChiCTR2000034780), will provide information placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2020; published online
Oct 15. https://doi.org/10.1016/S1473-3099(20)30831-8.
on whether this vaccine is safe and efficacious against 8 Sanders B, Koldijk M, Schuitemaker H. Inactivated viral vaccines.
SARS-CoV-2 infection, and for how long the protective In: Nunnally BK, Turula VE, Sitrin RD, eds. Vaccine analysis: strategies,
principles, and control. Berlin, Heidelberg: Springer Berlin, Heidelberg;
effect is maintained. 2015: 45–80.
9 Wang H, Zhang Y, Huang B, et al. Development of an inactivated vaccine
We declare no competing interests.
candidate, BBIBP-CorV, with potent protection against SARS-CoV-2.
Irina Isakova-Sivak, *Larisa Rudenko Cell 2020; 182: 713–21.
10 Jeyanathan M, Afkhami S, Smaill F, Miller MS, Lichty BD, Xing Z.
[email protected] Immunological considerations for COVID-19 vaccine strategies.
Institute of Experimental Medicine, Saint Petersburg 197376, Russia Nat Rev Immunol 2020; 20: 615–32.

What reinfections mean for COVID-19

One of the key questions in predicting the course of the infection (specimen A) and reinfection (specimen B)
COVID-19 pandemic, caused by severe acute respiratory differed significantly, making the chance of the virus
syndrome coronavirus 2 (SARS-CoV-2), is how well and being from the same infection small. What is worrisome
how long the immune responses protect the host from is that SARS-CoV-2 reinfection resulted in worse disease
reinfection. For some viruses, the first infection can than did the first infection, requiring oxygen support

Flickr - NIAID
provide lifelong immunity; for seasonal coronaviruses, and hospitalisation. The patient had positive antibodies
protective immunity is short-lived.1 after the reinfection, but whether he had pre-existing
In The Lancet Infectious Diseases, Richard L Tillett antibody after the first infection is unknown (table). Published Online
October 12, 2020
and colleagues describe the first confirmed case of This case report adds to rapidly growing evidence of https://doi.org/10.1016/
SARS-CoV-2 reinfection in the USA.2 A 25-year-old COVID-19 reinfection, in which viral genomic sequences S1473-3099(20)30783-0

man from the US state of Nevada, who had no known were used to confirm infections by distinct isolates of This online publication
has been corrected. The
immune disorders, had PCR-confirmed SARS-CoV-2 SARS-CoV-2. What do reinfection cases mean for public corrected version first
infection in April, 2020 (cycle threshold [Ct] value health and vaccination endeavors to stop the COVID-19 appeared at thelancet.
com/infection on
35·24; specimen A). He recovered in quarantine, testing pandemic? November 6, 2020
negative by RT-PCR at two consecutive timepoints Do reinfections occur because of a scant antibody See Articles page 52
thereafter. However, 48 days after the initial test, response after first infection? Of the four reinfection
the patient tested positive again by RT-PCR (Ct value cases reported to date, none of the individuals had
35·31; specimen B). Viral genome sequencing showed known immune deficiencies. Currently, only two indi­
that both specimens A and B belonged to clade 20C, a viduals had serological data from the first infection
predominant clade seen in northern Nevada. However, and one had pre-existing antibody (IgM) against
the genome sequences of isolates from the first SARS-CoV-2. Because of the wide range of serological

www.thelancet.com/infection Vol 21 January 2021 3

 Comment

Sex Age (years) First infection Second infection (Ct) Intervening Antibody after Antibody after
(Ct) period (days) first infection reinfection
Hong Kong3 Male 33 Mild (N/A) Asymptomatic (27) 142 Negative IgG+
Nevada, USA2 Male 25 Mild (35) Hospitalised (35) 48 N/A IgM+ and IgG+
Belgium4 Female 51 Mild (26–27) Milder (33) 93 N/A IgG+
Ecuador5 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.

Table: Characteristics associated with reinfection with SARS-CoV-2

testing platforms used across the globe, it is impossible reinfection by a distinct viral variant from the original
to compare results from one assay to another. For virus does not imply immune escape.
example, antibody reactivity to nucleocapsid protein Does immunity prevent transmission from those who
indicates previous exposure to SARS-CoV-2 but not are reinfected? The Ct value of PCR correlates with viral
whether antibodies that can block infection (anti-spike) load, and low Ct values (high viral load) might indicate
are present. Also, antibody levels are highly dependent infectiousness of the individual. Although Ct values can
on the timing after exposure. The key goal for the future vary substantially between various tests and laboratories,
is to ascertain the level and specificity of antibody to in one study, samples with Ct values greater than 35
spike protein at the time of reinfection, to determine were only 8% positive for cultivable virus.7 A good proxy
immune correlate of protection. for infectiousness can be obtained through viral plaque
Does immunity protect an individual from disease assays that measure the infectious virus. However,
on reinfection? The answer is not necessarily, because these assays require biosafety level 3 facilities and are
patients from Nevada and Ecuador had worse disease labour intensive, and the assays are not routinely done
outcomes at reinfection than at first infection. It is in clinical laboratories. Since some reinfection cases had
important to keep in mind that the reinfection cases in Ct values less than 35,3,4 infectious virus might have been
general are being picked up because of symptoms and harboured in the nasal cavity. Thus, reinfection cases tell
are biased towards detection of symptomatic cases. us that we cannot rely on immunity acquired by natural
Due to the paucity of broad testing and surveillance, we infection to confer herd immunity; not only is this
do not know how frequently reinfection occurs among strategy lethal for many but also it is not effective. Herd
individuals who recovered from their first infection. immunity requires safe and effective vaccines and robust
Asymptomatic reinfection cases can only be picked vaccination implementation.
up by routine community testing or at an airport, for As more cases of reinfection surface, the scientific
example,3 and we are probably severely underestimating community will have the opportunity to understand
the number of asymptomatic reinfections. Why do some better the correlates of protection and how frequently
reinfections result in milder disease,3,4 whereas others natural infections with SARS-CoV-2 induce that level
are more severe?2,5 Further investigation is needed of of immunity. This information is key to understanding
pre-existing immune responses before second exposure, which vaccines are capable of crossing that threshold to
and viral inoculum load. confer individual and herd immunity.
Does infection by different viral isolates mean we I declare no competing interests.
need a vaccine for each type? While differences in the Akiko Iwasaki
viral genome sequence of the various isolates are a [email protected]
great way to know if an individual is reinfected (ruling Department of Immunobiology, Yale University School of Medicine, New Haven,
CT 06520, USA; Department of Molecular Cellular and Developmental Biology,
out reactivation of lingering virus infection), it does Yale University, New Haven, CT 06510, USA; and Howard Hughes Medical
not indicate that the second infection was due to Institute, Chevy Chase, MD 20815, USA

immune evasion. There is currently no evidence that a 1 Edridge AWD, Kaczorowska J, Hoste ACR, et al. Seasonal coronavirus
protective immunity is short-lasting. Nat Med 2020; published online
SARS-CoV-2 variant has emerged as a result of immune Sept 14. https://doi.org/10.1038/s41591-020-1083-1.
evasion. For now, one vaccine will be sufficient to confer 2 Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection
with SARS-CoV-2: a case study. Lancet Infect Dis 2020; published online
protection against all circulating variants.6 Furthermore, Oct 12. https://doi.org/S1473-3099(20)30764-7.

4 www.thelancet.com/infection Vol 21 January 2021

 Comment

3 To KK-W, Hung IF-N, Ip JD, et al. COVID-19 re-infection by a phylogenetically 6 Dearlove B, Lewitus E, Bai H, et al. A SARS-CoV-2 vaccine candidate would
distinct SARS-coronavirus-2 strain confirmed by whole genome likely match all currently circulating variants. Proc Natl Acad Sci USA 2020;
sequencing. Clin Infect Dis 2020; published online Aug 25. 117: 23652–62.
https://doi.org/10.1093/cid/ciaa1275. 7 Singanayagam A, Patel M, Charlett A, et al. Duration of infectiousness and
4 Van Elslande J, Vermeersch P, Vandervoort K, et al. Symptomatic SARS-CoV-2 correlation with RT-PCR cycle threshold values in cases of COVID-19,
reinfection by a phylogenetically distinct strain. Clin Infect Dis 2020; published England, January to May 2020. Euro Surveill 2020; 25: 2001483.
online Sept 5. https://doi.org/10.1093/cid/ciaa1330.
5 Prado-Vivar B, Becerra-Wong M, Guadalupe JJ, et al. COVID-19 re-infection
by a phylogenetically distinct SARS-CoV-2 variant, first confirmed
event in South America. SSRN 2020; published online Sept 8.
https://doi.org/10.2139/ssrn.3686174 (preprint).

COVID-19 in malaria-endemic regions: potential consequences

for malaria intervention coverage, morbidity, and mortality
COVID-19 has had a massive impact on the populations malaria burden, Ghana and Nigeria reported absolute Published Online
September 21, 2020
and economies of the world. As of Sept 9, 2020, increases in the number of malaria cases, while case https://doi.org/10.1016/
the virus has infected more than 27 million people numbers did not change substantially in seven countries S1473-3099(20)30763-5

in 216 countries and territories worldwide, and the and only Uganda reported a decrease.3 Given that this See Articles page 59

number of deaths is approaching a million.1 Although deceleration could be compounded by the COVID-19
the spread of COVID-19 to Africa has been slow and pandemic, there is an urgent need to quantify and
its direct impact in Africa is below the level seen in analyse the potential impact of the pandemic on malaria
other continents, the potential effects of COVID-19 on control and intervention strategies.
strategies and methods to combat other diseases such as In The Lancet Infectious Diseases, Daniel Weiss and
malaria—which pose significant burdens on substantial colleagues12 quantified the indirect effects of COVID-19
proportions of the world and the African population, on the distribution of ITNs and on access to effective
and especially children—are a cause for great concern. antimalarial drugs—two key components of malaria
Thus, understanding how the COVID-19 pandemic could control in Africa. Using a range of counterfactual
indirectly affect malaria control intervention strategies scenarios based on different levels of reduction in
is urgent in all malaria-endemic regions, and especially ITN and antimalarial drug coverage, the authors
those that are part of WHO’s “high burden to high estimated the additional morbidity and mortality
impact” initiative.2 due to malaria that might be seen in the year 2020
Since 2010, active malaria intervention control stra­ across malaria-endemic Africa. Current data were used
tegies have had a positive effect on lowering malaria to generate geospatial estimates of malaria infection
burden and morbidity in Africa and worldwide. These prevalence, clinical case incidence and mortality,
strategies include the use of long-lasting insecticide- Plasmodium falciparum parasite rates, ITN coverage,
treated nets (ITNs), indoor residual spraying,4 and and effective treatment availability. The anticipated
timely access to antimalarial drugs, including the use malaria burden in the absence of COVID-19 disruptions
of intermittent preventive treatment aimed at killing served as a baseline for comparison. On the basis of
forms of the malaria parasite in infected individuals,5–7 in their estimates, Weiss and colleagues concluded that
addition to the other mechanisms aimed at disrupting COVID-19-related disruptions to malaria control
the transmission of malaria by exploiting the feeding efforts in Africa could lead to significant reversals of the
behaviour and gonotrophic and reproductive cycles of progress made over the past two decades in reducing
mosquitoes.8–11 However, despite the progress of the past malaria morbidity and mortality, with a possibility
decade, evidence suggests that the rate of reduction of a near doubling in mortality due to malaria under
in malaria mortality in the WHO African Region has the worst case scenario (combined reductions of
slowed since 2016, although total deaths due to malaria 75% in effective antimalarial treatment and 75% in
decreased overall.3 In particular, from 2017 to 2018, routine ITN distribution, with no mass ITN distribution
among the ten African countries with the highest campaigns).12

www.thelancet.com/infection Vol 21 January 2021 5