Why is COVID-19 highly transmissible?

In the early stages of mild coronavirus disease 2019 (COVID-19) cases, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to replicate actively and rapidly in the upper respiratory tract, according to a new study.

“Critically, the majority of patients in the present study seemed to be already beyond their shedding peak in upper respiratory tract samples when first tested,” researchers said. “Together, these findings suggest a more efficient transmission of SARS-CoV-2 than SARS-CoV through active pharyngeal viral shedding at a time when symptoms are still mild and typical of upper respiratory tract infection.”

Nine patients presenting with mild or prodromal COVID-19 symptoms were confirmed to be infected by SARS-CoV-2 through reverse transcriptase-polymerase chain reaction (RT-PCR). Over the first 5 days of infection, testing revealed an average viral RNA load of 6.76x10⁵ copies per whole swab; the maximum RNA level measured was 7.11x10⁸ copies per swab. [Nature 2020;doi:10.1038/s41586-020-2196-x]

Beyond day 5, the average viral RNA load dropped to 3.44x10⁵ copies per swab, coupled with a detection rate of 39.93 percent. The swab sample that tested positive was collected 28 days after onset of symptoms.

The researchers also attempted to isolate live viruses from swab and sputum samples, to assess infectivity. Through the first week of symptoms, viruses were readily isolated from 16.66 percent of swabs and 83.33 percent of sputum samples. By day 8 and beyond, despite consistently high viral RNA loads, no live isolates could be obtained.

Moreover, all throughout the study duration, the researchers were unable to isolate viruses from stool samples. None of the urine or serum samples collected also tested positive for SARS-CoV-2 RNA.

“High viral loads and successful isolation from early throat swabs suggested potential virus replication in upper respiratory tract tissues,” they noted. This was confirmed through more RT-PCR tests and full viral genome sequencing, which found different polymorphism signatures in sputum and swab samples collected from the same patient on the same day.

“The presence of separate genotypes in throat swabs and sputum strongly supported our suspicion of independent virus replication in the throat, rather than passive shedding there from the lung,” the researchers explained.

Viral loads in sputum, swab and stool samples generally peaked early but waned slowly. In all but one of the patients, viral RNA in throat swabs seemed to already be declining by the time the first symptoms appeared. In sputum and stool samples, the highest RNA levels were generally observed during the first week of symptoms, followed by a more gradual decrease.

“Whereas symptoms mostly waned until the end of the first week, viral RNA remained detectable in throat swabs well into the second week,” the researchers said. “Stool and sputum samples remained RNA-positive over 3 weeks in six of the nine patients, in spite of full resolution of symptoms.”

Interestingly, the clinical course of the disease did not align well with the adaptive immune response. While seroconversion had occurred in all patients by day 14, no abrupt virus elimination was observed.

This suggests that “vaccine approaches targeting mainly the induction of antibody responses should aim to induce particularly strong antibody responses in order to be effective,” the researchers said.

Key weaknesses of the present study include its small sample size and the lack of severe COVID-19 cases, they added. “Future studies including severe cases should look at the prognostic value of an increase of viral load beyond the end of week 1, potentially indicating aggravation of symptoms.”