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Deadly or not, we still have much to learn about Omicron

South Africa was the first to identify the new variant now known as Omicron. The country has a world-class infectious diseases surveillance system, which allowed quick identification of the variant. (Photo: Bloomberg)Premium
South Africa was the first to identify the new variant now known as Omicron. The country has a world-class infectious diseases surveillance system, which allowed quick identification of the variant. (Photo: Bloomberg)

  • Preliminary reports have led to the assumption that the disease caused is clinically milder. But …
  • One silver lining is that drugs that are currently being used to treat covid-19, or are in late-stage clinical trials, are not expected to be adversely impacted by Omicron

ARLINGTON (VIRGINIA) : Omicron (B.1.1.529) is a new variant of concern first identified in Botswana and reported to the World Health Organization (WHO) by South Africa on 24 November. At the time of writing, this variant is spreading across the world, though whether it will outcompete and ultimately overtake Delta as the prevailing strain in the world is not known.

WHO acted with alacrity in designating Omicron a variant of concern out of an abundance of caution, not because much was known about how it spreads or how severe the disease it causes, but because of its many mutations which potentially allow the virus to act differently from known variants.

Many countries in the world have taken drastic steps including halting travel from African countries where the variant has been spotted. Travel restrictions are contentious and should only be applied judiciously and for a short time until more is known about the clinical and transmission features of a variant. If there is cryptic spread in the community and cases appear with no discernable travel history to affected countries, they are of limited utility. A travel restriction instituted after community spread has been identified is like shutting the barn door after the horse has already bolted. South Africa has a world-class infectious diseases surveillance system, which allowed the country to identify the variant and report it very quickly. Now, with the country facing economic hardship due to restrictions placed on travel, many feel that they are being needlessly punished for doing the right thing.

Omicron is highly mutated, which means that it has many changes to its genetic material compared to the original SARS-CoV-2 virus that was identified in Wuhan, China. It also has many more mutations than the prevailing variants of concern. Some of these changes may have no biological significance, but others are likely to result in changes to amino acid building blocks of proteins. This does not mean that it is a different virus altogether, but that some of the biological features may be different.

Proteins are the workhorse molecules of life. SARS-CoV-2 has over two dozen proteins. The one that you hear about most is the spike protein because it allows the virus to enter cells and is also a target for antibodies generated after vaccination. The spike protein is found in an array on the surface of the virus where it acts as a “key" that opens human cells that have a specific “lock" called the ACE2 receptor. The key of the virus that was first identified in Wuhan fit the cellular lock reasonably well (and better than the original SARS coronavirus). This was one of the reasons why it was able to cause a pandemic.

But as the virus infected more people, it randomly changed and improved its ability to get inside cells and make copies of itself. This led to better viral replication and greater transmission efficiency in a variant like Delta that became dominant worldwide in 2021. Some of the changes also led to more reinfections and reduced recognition by antibodies generated from approved vaccines. We do not know much about Omicron yet, but these are the concerns we have with this new variant.

A weaker immune response?

The vaccines currently being used were created to elicit an immune response against the virus identified in Wuhan. As viruses mutate and change shape over time, the features recognized by antibodies generated after infection or vaccination also change. This does not mean that variants become vaccine-proof. It may mean that a booster dose or a modified vaccine that recognizes the changes will need to be administered to offer full protection.

At present, we do not know the extent of protection of those who are fully vaccinated against Omicron. We do not know how well the variant spreads in a vaccinated population compared to an unvaccinated one. Scientists are racing to answer these questions. As we get the information, we will find out in real-world how many people who were vaccinated are getting infected with Omicron. Here also, preliminary data from South Africa indicates that the unvaccinated are more likely to be infected.

Researchers will first test how well antibodies from blood samples of those who have been vaccinated with earlier vaccines are capable of neutralizing the variant. Vaccines were created to generate polyclonal antibodies that recognize different parts of the spike protein. If the protein is significantly changed, recognition by antibodies will drop. Because of its extensive changes, it is likely that antibodies will show reduced neutralization ability against Omicron. If neutralizing antibody amounts decline with the variant, one option is to offer a booster of the earlier vaccine at the same dose or even at a higher dose to “top-up" antibody levels. Vaccine manufacturers are testing this approach.

It is worth noting that antibody recognition has decreased with other variants too. The threshold to which antibodies prevent infection differs in different people. The drop in neutralizing ability may also vary. Loss of neutralization shouldn’t be equated with total loss of immunity.

Another important point: neutralization experiments err on the side of caution, since they do not consider the other arm of the immune response—cell-mediated immunity which kicks in to prevent severe disease. If antibodies are the army of the immune system, humans also have a navy and an air force.

Complete abrogation of an immune response is possible with a heavily mutated virus, but this seems unlikely based on current knowledge. With other SARS-CoV-2 variants, in addition to antibodies, other components of the immune system such as T cells help reduce the severity of infection after vaccination.

In the coming weeks, more will be known about the Omicron variant, but vaccine manufacturers already have a head start. They have started to work on modified vaccines. Vaccine manufacturers are also creating bivalent vaccines that recognize parts of different variants. As more variants arise in the future, annual boosters with modified vaccines may be necessary. The ultimate hope is that super-vaccines that recognize parts of variants and different coronaviruses will be available in a few years.

The mRNA vaccines in particular are easy to adapt since the delivery mechanism remains the same. Only the “message" needs to be modified. Pfizer has indicated that it can ship the first batches of any new vaccine (should one be required) in 100 days. Viral-vectored vaccines (such as Oxford/AstraZeneca/Covishield) are easy to design but require a bit more work to produce at scale.

It is not known yet how people who were infected with other variants will fare when exposed to Omicron. The immune response after infection is heterogenous and depends on many factors including age, health, and whether the infection was asymptomatic or symptomatic. But unlike most vaccines, antibodies after natural infection would be generated to other proteins of the virus apart from the spike protein.

Inactivated virus vaccines also generate antibodies to parts of the virus other than the spike protein. While these may not prevent infection (since the spike protein is the key viral protein that mediates this step), they may reduce the severity of disease. Covaxin, which is an inactivated virus vaccine, may continue to be durable in preventing severe disease against Omicron. However, this warrants further examination.

Drugs might still work

Convalescent plasma has not been found to work for SARS-CoV-2 or any of the other variants and should not be used for Omicron. Monoclonal antibodies that target the spike protein will likely need to be updated since they are very specific to parts of the coronavirus spike protein.

One silver lining is that drugs that are currently being used to treat covid-19 (or are in late-stage clinical trials) are not expected to be adversely impacted by Omicron since they do not target the viral spike protein. The majority of the mutations in Omicron that have gathered interest are in the spike protein but there are mutations in other viral proteins, so this will still need to be tested.

Merck’s molnupiravir is an oral antiviral that thwarts the viral replication process. The drug is a dummy for a key piece that the virus needs to insert into genetic material as it makes copies inside cells. Molnupiravir gets embedded into viral RNA and so defective viral parts are created. And the drug seems to be generally variant-resistant. In some ways, the mode of action of molnupiravir is similar to an earlier antiviral, remdesivir. However, molnupiravir is available in pill-form. There’s some debate as to the efficacy of molnupiravir (and Merck recently reported a drop in risk reduction from 50% to 30%). Other trials conducted in India by other companies were halted.

Pfizer has a combination antiviral that targets a different protein called the main protease. The main protease is an enzyme that coronaviruses need to infect cells, so it is an attractive drug target. This therapy uses ritonavir, an antiviral previously used for HIV, and ties it up with a new small molecule that originated in Pfizer’s own laboratories. This is an oral antiviral designed to be used at the first sign of infection. If approved, this could serve as a line of defence against Omicron as well as other variants.

Approved steroid drugs like dexamethasone have limited indications for use in severe covid-19, but they are also unlikely to be impacted by Omicron.

Omicron’s severity

Preliminary reports from South Africa and elsewhere have led to the assumption the disease caused by Omicron is clinically milder. This would be excellent news since the severity of the symptoms will ultimately determine the stringency of the public health response. However, the demographics of the population here also matters since we know that covid-19 does not impact all populations equally. Young, healthy people are likely to have milder covid-19 regardless of the variant. South Africa has a relatively young population compared to many other nations.

It is appealing to think that the clinical symptoms are milder, but whether or not this is due to the biological properties of the virus is not known right now. The severity of an infectious disease is determined not only by the virus but also by the health and immune response of the host and the environment.

Determining the clinical severity of a virus that presents itself differently across the spectrum from asymptomatic to critical covid-19 is difficult until many infections have been studied. South Africa is 25% vaccinated and has gone through multiple covid-19 waves with earlier variants. If the rate of reinfections is relatively high, then those are cases in which we would expect less severe symptoms (assuming there was some immune protection from earlier variants).

Omicron has replaced other variants that have been sequenced in South Africa, but the country was going through a dip in cases at the time. Whether or not the current rise is due to more transmission with Omicron will not be known until the spread of the variant has been tracked for longer. Some variants arise due to chance events, and do not end up overtaking others.

Epidemiological studies will trace the spread of Omicron where Delta is already established. If there’s no difference in the way people interact and the percentage of infections with Omicron increases, it would mean that this variant is outcompeting Delta. That would certainly be a cause for concern.

In the meantime, vaccinated people should wear properly fitting masks, practise social distancing, and avoid crowded settings. Current vaccines may not prevent infections or prevent mild or moderate symptomatic covid-19. But they will continue to serve their key purpose if they can keep people out of hospitals and prevent deaths.

Anirban Mahapatra, a microbiologist by training, is the author of COVID-19: Separating Fact From Fiction. These are his personal views.

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