We are in the third wave of COVID-19 and the future is once again very uncertain. The new coronavirus has come to stay, that is clear. We can predict that, in a scenario of partial efficacy of vaccines and absence of infection in more than 70% of the population , an end to the pandemic is not predicted for 2-3 years. Only by then will reinfections be the norm and will mostly only cause colds. SARS-CoV-2 will have become one of the endemic coronaviruses that cause colds in winter.
New variants of immune escape
The original strain described in Wuhan – it seems that after a jump to humans from the reservoir in bats – has been adapting to the population throughout the months of the pandemic. In April, he acquired a D614G mutation in the spicular protein (‘S’, spike) of the viral envelope, which gave him an advantage in transmission.
In England the variant B.1.1.7 emerged, which has been distributed almost all over the world. It is transmitted more because a group of mutations in the ‘S’ protein make it more easily attach to the ACE2 receptor on human airway cells. The N501Y mutation seems to be the main responsible for its greater contagiousness, due to an increase in the affinity of the virus to the cellular receptor.
Independently, in South Africa the variant B.1.351 was described a few weeks ago, which incorporates more mutations in the ‘S’ protein. Among them is the N501Y mutation, already described in the British variant and associated with greater transmissibility. However, the South African variant also has an E484K mutation that alters the recognition site of antibodies produced against SARS-CoV-2, both in natural infection and after the administration of current (or first-generation) vaccines. . It is the main responsible for the lower susceptibility to antibodies. These mutations could cause a lower efficacy of the vaccines and / or favor reinfections.
More recently, in patients from the Amazon in Brazil, the P.1 variant has been described, close to the South African variant, with which it shares the N501Y and E484K mutations, which confer greater transmissibility and immune escape, respectively. In view of this information, both Moderna and Pfizer have come forward saying that they are already developing new vaccines with activity against these new variants of SARS-CoV-2.
Finally, in California, the isolation of a new CAL.20C variant has been reported, which has an L452Y mutation, which confers greater transmissibility.
RNA viruses, quasispecies and mutations
The recognition of immune escape mutations in the COVID-19 coronavirus should not be considered surprising. Genetic variability in coronaviruses follows the pattern of other RNA viruses, such as HIV or the hepatitis C virus. They behave as quasispecies, that is, a heterogeneous set of genetic sequences, all similar to a standard sequence (or consensus) , which evolve over time in infected subjects.
Although there is a nuclease that corrects errors during the replication of SARS-CoV-2, the constellation of mutants that occur daily is very high, so that most of the mutations that confer immune escape and / or resistance to antivirals pre-exist. Even before vaccines or drugs are given!
New antivirals against the coronavirus
Currently, the therapeutic arsenal against COVID-19 is restricted to corticosteroids and remdesivir. Steroids are anti-inflammatory and reduce the progression to bilateral pneumonia and cytokine storm complications that can appear 7-10 days after initial infection. Remdesivir is an inhibitor of viral RNA polymerase, although it has little antiviral potency.
In an attempt to end the treatment shortage, the activity of plitidepsin (Aplidin) has been explored. It is a molecule that inhibits the cytoplasmic protein EF1A in infected cells, which is recruited for the synthesis of the viral nucleocapsid. Could it be effective? In the United States, a group of researchers led by the Spanish Alfredo García-Sastre has published in Science that plitidepsin has an antiviral potency in vitro more than 25 times higher than remdesivir. Although this is great news, the results need to be confirmed by other groups and it remains to be seen whether they can be extrapolated to humans.
Plitidepsin was originally approved in 2018 in Australia for the salvage treatment of multiple myeloma, a hematologic cancer. It is administered intravenously. The demonstration that it has antiviral activity against SARS-CoV-2 is encouraging. It opens the doors to consider the possibility of using the drug and its derivatives for the treatment of COVID-19. Or even for the prevention of contagion, through aerosol and / or prolonged-release formulations, which could function as ‘chemovaccines’ or pre-exposure prophylaxis (PrEP), in a similar way to what we do in HIV infection.
In any case, it seems indisputable that the development of new and more powerful antivirals against SARS-CoV-2 is a priority. Of special urgency in view of the proliferation of immune escape variants.
Vicente Soriano, Faculty of Health Sciences & Medical Center, UNIR – International University of La Rioja
This article was originally published on The Conversation. Read the original.
