A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus,, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.
“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.
Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.
A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
Little optimism about antivirals’ impact
Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.
“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”
He noted that in ain 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.
A National Institutes of Healthannouncing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.
“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.
Fellow panelist, concurred.
“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.
Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).
Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.