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By Christian Hoffmann &
Bernd S. Kamps

29 July

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Epidemiology

McNeil Jr DG. A Viral Epidemic Splintering Into Deadly Pieces. The New York Times, 29 July 2020. Full-text: https://www.nytimes.com/2020/07/29/health/coronavirus-future-america.html

This is not a scientific paper, but it is better than two thirds of published and pre-published articles about COVID-19 epidemiology. More than 4,000 words thoughtfully put down by Donald G. McNeil Jr. If you don’t read it now, read it on the weekend.

 

Virology

Chen J, Malone B, Llewellyn E, et al. Structural basis for helicase-polymerase coupling in the SARS-CoV-2 replication-transcription complex. Cell 2020, 27 July, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.07.033

The SARS-CoV-2 genome is replicated and transcribed by the RNA-dependent RNA polymerase holoenzyme (subunits nsp7/nsp8₂/nsp12) along with accessory factors such as the nsp13 helicase. Elizabeth A. Campbell, Seth A. Darst and colleagues now present a cryo-electron microscopic structure of the SARS-CoV-2 holo-RdRp with an RNA template-product with two molecules of the nsp13 helicase and identify a new potential target for future antiviral drugs.

 

Transmission

Sekizuka T, Itokawa K, Kageyama T, et al. Haplotype networks of SARS-CoV-2 infections in the Diamond Princess cruise ship outbreak. PNAS 2020, published 28 July. Full-text: https://doi.org/10.1073/pnas.2006824117

We remember the Diamond Princess: a cruise ship put under quarantine off of Yokohama, Japan, in early February. Of around 3,700 people on board, more than 700 people became infected with SARS-CoV-2 and seven patients died. Now, after whole-genome sequencing of SARS-CoV-2 and a network/phylogeny analysis of the outbreak, Makoto Kuroda and colleagues conclude that there was a single introduction of SARS-CoV-2, which disseminated among passengers on the ship through possible mass-gathering events in the recreational areas where people dance, sing, watch performances, or shop.

 

Immunology

Braun J, Loyal L, Frentsch M, et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature 2020, published 29 July. Full-text: https://doi.org/10.1038/s41586-020-2598-9

Induction of SARS-CoV-2-specific CD4+ T cells is likely to be critical in the instruction of potentially protective antibody responses. Andreas Thiel, Leif-Erik Sander, Claudia Giesecke-Thiel and colleagues therefore investigated SARS-CoV-2 spike glycoprotein (S)-reactive CD4⁺ T cells in peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors (HD). Surprise: they detected SARS-CoV-2 S-reactive CD4⁺ T cells in 83% of patients with COVID-19 but also in 35% of unexposed HD. These data raise the intriguing possibility that pre-SARS-CoV-2 S-reactive T cells represent cross-reactive clones, probably acquired during previous infections with endemic human coronaviruses (HCoVs) such as 229E and OC43. The biological role of such pre-existing S-cross-reactive CD4+ T cells in 35% of HD still remains unclear. However, assuming that these cells have a protective role in SARS-CoV-2 infection, they may contribute to divergent manifestations of COVID-19 and explain the resilience of children and young adults to symptomatic SARS-CoV-2 infection (more frequent social contacts than people from older age groups and thus a higher HCoV prevalence). This hypothesis remains to be validated in larger cohorts. The authors don’t forget to underline that the presence of S-cross-reactive T cells in a sizable fraction of the general population may have important implications for the design and analysis of upcoming COVID-19 vaccine trials.

 

Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol 2020, published 29 July. Full-text: https://doi.org/10.1038/s41577-020-0402-6

Will T cells provide long-term protection from reinfection with SARS-CoV-2? Nobody knows yet. Now Zeyu Chen and E. John Wherry from Philadelphia review recent studies which have shed light on T cell responses to SARS-CoV-2 infection. Accumulating evidence supports a role for T cells in COVID-19 and probably in the immunological memory after SARS-CoV-2 infection. Multiple distinct patterns of T cell response may exist in different patients and the authors suggest that the possibility of distinct clinical approaches may one day be tailored to the particular immunotype of a specific patient.

 

Vaccine

Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med 2020, published 28 July. Full-text: https://doi.org/10.1056/NEJMoa2024671

Vaccination of non-human primates with mRNA-1273 induces robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. For this important vaccine trial, Barney S. Graham, Robert A. Seder and colleagues divided 12 female and 12 male Indian-origin rhesus macaques into groups of three and vaccinated them intramuscularly at week 0 and at week 4 with either 10 or 100 μg of mRNA-1273 or placebo. At week 8 (4 weeks after the second vaccination), all animals were challenged with SARS-CoV-2. mRNA-1273 induced antibody levels exceeding those found in human convalescent phase serum. Vaccination also induced type 1 helper T cell (Th1)–biased CD4 T cell responses and low or undetectable Th2 or CD8 T cell responses.

No viral replication was detectable in the nose of any of the eight animals in the 100 μg dose group by day 2 after challenge (8 weeks after the first vaccination). The ability to limit viral replication in both the lower and the upper airways will have important implications for vaccine-induced prevention of both SARS-CoV-2 disease and transmission.

 

Liu G, Carter B, Bricken T, Jain S, Viard M, Carrington M, Gifford DK. Computationally Optimized SARS-CoV-2 MHC Class I and II Vaccine Formulations Predicted to Target Human Haplotype Distributions. Cell Systems 2020, published 27 July. Full-text: https://www.cell.com/cell-systems/fulltext/S2405-4712(20)30238-6

Do you want to optimize peptide vaccine formulations for SARS-CoV-2? David K. Gifford and colleagues from MIT now give you a combinatorial machine learning method. They also encourage the early publication of vaccine designs to enable collaboration and rapid progress toward safe and effective vaccines for COVID-19. Consequently, they provide an open-source implementation of their design methods (OptiVax), vaccine evaluation tool (EvalVax), as well as the data used in their design efforts: https://github.com/gifford-lab/optivax.

 

Clinical

Karagiannidis C, Mostert C, Hentschker C, et al. Case characteristics, resource use, and outcomes of 10 021 patients with COVID-19 admitted to 920 German hospitals: an observational study. Lancet Respir Med 2020, published 28 July. Full-text: https://doi.org/10.1016/S2213-2600(20)30316-7

In this observational study, Christian Karagiannidis and colleagues report on 10,021 adult patients with a confirmed COVID-19 diagnosis, who were admitted to 920 hospitals in Germany between 26 February and 19 April 2020. The median age was 72 years. 1727 patients (17%) needed mechanical ventilation. The main findings:

• Patients on mechanical ventilation had more comorbidities than patients without mechanical ventilation
• Mortality was 53% in patients being mechanically ventilated, reaching 63% in patients aged 70–79 years and 72% in patients aged 80 years and older
• Mortality was 73% in patients requiring both ventilation and dialysis

 

Table 1. Mortality in patients of the German AOK study.
	Mortality
No ventilation	16% (1323/8294)
With ventilation	53% (906/1727)
With ventilation + dialysis	78% (324/469)

 

Comorbidities

Nishiga M, Wang DW, Han Y et al. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020, published 20 July. Full-text: https://doi.org/10.1038/s41569-020-0413-9

Pre-existing cardiovascular disease is linked with higher morbidity and mortality in patients with COVID-19, whereas COVID-19 itself can induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism. In this review, Masataka Nishiga, Joseph C. Wu and colleagues summarize the current understanding of the interaction between COVID-19 and the cardiovascular system.

 

Society

Kupferschmidt K. ‘Vaccine nationalism’ threatens global plan to distribute COVID-19 shots fairly. Science 2020, 28 July. Full-text: https://www.sciencemag.org/news/2020/07/vaccine-nationalism-threatens-global-plan-distribute-covid-19-shots-fairly

‘We will not sell it at cost.” (We will sell it for profit.) That was the statement, a few days ago, of a company that is receiving almost 1,000,000,000 dollars from US tax payers for the development of a COVID-19 vaccine. Fortunately, other companies, too, are producing vaccines and good old WHO and other international organizations have set up a system to accelerate and equitably distribute vaccines, the COVID-19 Vaccines Global Access (COVAX) Facility. Kai Kupferschmidt summarizes the current state-of-affairs.

 

Beyond plate borders

Stone R. Siberia’s ‘gateway to the underworld’ grows as record heat wave thaws permafrost. Science 2020, 28 July. Full-text: https://www.sciencemag.org/news/2020/07/siberia-s-gateway-underworld-grows-record-heat-wave-thaws-permafrost

Global warming is inflicting wounds across Siberia. Outbursts of pent-up methane gas in thawing permafrost have pocked Russia’s desolate Yamal and Gydan peninsulas with holes tens of meters across. Apartment buildings are listing and collapsing on the unsteady ground, causing about $2 billion of damage per year to the Russian economy. Follow Richard Stone on a trip through climate-changed Siberia.