The vaccine Russia gave provisional approval to on August 11 has shown favorable outcomes in a small, non-randomized study. The data was published in The Lancet on Friday, two days after the World Health Organization issued a strong recommendation for the use of steroids among seriously ill COVID-19 patients based on the results of seven clinical trials.
Russian vaccine
Between June 18 and Aug. 3, 2020, Russian scientists enrolled 76 healthy adults aged 18 to 60 in two Phase I/2 trials. Both studies assessed the effectiveness and safety of the vaccine, which comprises two components—a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for SARS-CoV-2 spike glycoprotein. In Phase I of each study, one dose of the vaccine was administered intramuscularly with continuous monitoring for 28 days. On day 21, for Phase 2, the volunteers were given a prime-boost vaccination.
According to the study results, all participants produced antibodies to the SARS-CoV-2 glycoprotein. During Phase I of both studies, SARS-CoV-2 antibodies were detected on day 14 in 89% of those administered rAd26 and 84% in those who received rAd5. During Phase 2, antibodies were detected in 85% of volunteers on day 14 and 100% of participants on day 21. Additionally, boosting with rAd5 showed an increased in SARS-CoV-2 antibodies: 5,322 compared with 1,866 seven days post-boost vaccination.
As the researchers report, most adverse effects were mild with no serious side effects detected. The most common adverse effects were pain at injection site (58%), hyperthermia (50%), headache (42%), asthenia (28%), and muscle and joint pain (24%).
That being said, there were numerous limitations to the study, including the short duration of follow-up (42 days) inclusion of only male volunteers in some parts of Phase I, extremely low number of participants, and no control vaccine. Additionally, the age of the participants skewed heavily toward young persons.
This Phase 1/2 clinical study of 76 participants is what allowed the Russian government to approve the vaccine for provisional licensure in early August. And while provisional licensure does allow the vaccine to be used in some volunteers and throughout high-risk groups, it also requires a large-scale study of the general population. The researchers say the Phase 3 clinical trial, which involves 40,000 volunteers from different age and risk groups, was approved on Aug. 26, 2020 and will begin soon.
“The phase 3 clinical trial will be undertaken with constant monitoring of the condition of volunteers through an online application, and each dose of vaccine will have its own QR code, which will be assigned to the volunteer,” the researchers explain in their paper.
Corticosteroids
A meta-analysis of seven clinical trials across 12 countries has concluded corticosteroids are associated with lower mortality among critically ill patients with COVID-19, when compared with usual care or placebo. Corticosteroids are a cheap and widely available class of drugs, making them a perfect pandemic treatment if effective.
A total of 1,703 patients (mostly male) randomized to steroids, placebo or standard care were included in the meta-analysis. According to the results, there were 222 deaths among 678 patients who received corticosteroids and 425 deaths among 1,025 patients who received usual care or placebo. This corresponds to an absolute mortality risk of 32% with corticosteroids compared with an assumed mortality risk of 40% with usual care or placebo.
Dexamethasone and hydrocortisone were evaluated in all 7 clinical trials, and showed the highest efficacy rates. Methylprednisolone was assessed in only one clinical trial, and did not show as high a rate as the others. Additionally, a low dose of corticosteroids was found to be more effective than a high dose—patients who received a low dose were 7% less likely to die than those given a higher dose, and 11% less likely than those given usual care or a placebo.
Patients already on ventilators when treated with steroids did not fare as well as those who did not require ventilation. Those on ventilators had a 30% chance of dying compared with a 38% chance in the standard care/placebo group. For patients treated without ventilators, the treatment was more effective: 23% compared with 42%.
The results of the trials and meta-analysis led WHO to make “a strong recommendation” for the use of dexamethasone and hydrocortisone for 7 to 10 days in patients with severe and critical COVID-19.
“Given the moderate-certainty evidence of an important reduction in the risk of death, the panel concluded that all or almost all fully informed patients with severe or critical COVID-19 would choose treatment with systemic corticosteroids,” WHO wrote in their recommendation.
However, the organization said not to use corticosteroid therapy in patients with non-severe COVID-19, pointing to studies that have shown “low-certainty evidence” that suggests a potential increase of 4% mortality among COVID-19 patients who are not severely ill.