The Omicron threat

Omicron is coming fast. The extent to which it bypasses natural immunity obtained by prior exposure to Delta, and the extent by which it bypasses the immunity conferred by vaccination are of paramount relevance.

Highly infectious Omicron variant of coronavirus has brought back the fears of possible third wave in India. First detected in South Africa, the new variant has now spread in nearly 100 countries. Many European countries have witnessed sharp rise in Covid infection, mostly driven by Omicron.

As we close the edition, the number of Omicron cases has crossed the 350-mark in India across 12 states, and cases are rising every day. The country’s tally of Omicron cases has nearly doubled within a week, but there have been no deaths reported so far. In less than 40 percent of cases, patients either fully recovered or were discharged. Overall, the country has reported 34.75 million cases, the second-highest behind only the United States.

Now the country has sero-prevalence of 75–80 percent, first dose for 85 percent of adults, both doses for 55 percent of adults, and a reach for the pandemic of 95 percent. Yet, some 108 million adults remain unvaccinated, despite supplies of the shot being plentiful. Scientists say the experiences of Britain, the US, and Europe show that Omicron cannot be stopped by vaccinations alone. But the fact that so many Indians caught the virus earlier this year amid the country’s devastating second wave – and will still have some level of natural immunity – offers a sliver of hope.

On November 26, 2021, WHO reached deeper into the Greek alphabet and declared Omicron, the new SARS-CoV-2 variant of concern. The world’s reaction has been an unpleasant mixture of dread, fatigue, and déjà vu. Almost two years into a pandemic that has claimed more than five million lives and affected billions more, people everywhere are finding it hard to summon the energy for another chapter in the story.

Endemicity is still the goal. However, the Omicron variation is currently revising the timetable at the time of writing. Omicron rapidly became the dominant variant in South Africa, whether because it is more infectious or has a greater ability to avoid the immune system, or both. Data on the severity of the disease it produces is varied so far – some early data hint to a moderate clinical course, while other research suggests that Omicron may cause children to be hospitalized more frequently than other variants.

As of December 15, 2021, Omicron has so far been detected in 63 countries, and is surging in many of them. There is preliminary evidence, including from South Africa and the United Kingdom, that Covid-19 vaccines are less effective against Omicron than against Delta in preventing illness. The good news is that emerging data show that a booster dose restores high levels of vaccine effectiveness. The bad news is that too many people in the world have not had any doses of vaccine at all. Worldwide strategies are needed to enhance vaccine equity and access and to scale up other protective measures alongside vaccines. Early evidence also suggests that unvaccinated people who have been infected with the virus in the past are not well-protected against Omicron – re-infection appears to be common.

Given all of these initial data, the WHO calls Omicron a high-risk variant that could lead to further surges worldwide with severe consequences. What might these surges look like?

A massive spike in cases worldwide could be hugely disruptive and could lead to increased deaths. Even in the best-case scenario, in which Omicron causes a mild illness, the repercussions could be huge. Imagine, for example, that the entire world caught a cold at the same time. There would be a rise in deaths among older, vulnerable people – such as those in nursing homes – and the mass absences from work would have major societal consequences. Even if only a small percentage of people gets ill or die, a small percentage of a very large number would still be a large number. And in many nations, there is no slack in the health system to deal with another surge in Covid-19 hospitalizations. Hospitals are already at capacity, dealing not just with Covid-19 but with catching up on a backlog of surgeries and other treatments, delayed or deferred by the pandemic. Yet, there is no need for fatalism. Unlike the start of the pandemic, healthcare industry now has a wide range of science-based tools that one can and must marshal.

In any scenario for the future of the Covid-19 pandemic, much depends on the ways in which societies respond. Three levers are likely to be especially important, starting with the extent to which countries can effectively scale and make available new oral therapeutics with the potential to reduce the chance of progression to severe disease, and which are unlikely to be blunted by Omicron. Second, evidence is accumulating that booster doses are especially important for protecting against the Omicron variant; accelerating their rollout will help protect populations. And third, given public fatigue and the lessons of the past two years, finding the right combination of public-health measures will be critical.

The Omicron variant. Three main factors determine the real-world impact of any new SARS-CoV-2 variant – the extent to which it can evade the immunity developed by those who have been vaccinated or previously infected by other variants, its inherent infectiousness (often expressed as a higher basic reproduction number, or RO), and the severity of disease caused. The first two factors combine to drive the number of cases, while the third determines the number of severe cases and deaths. For example, the Delta variant, which remains dominant in most of the world, was significantly more transmissible than previously circulating variants were, showed limited incremental evasion of immunity, and caused moderately more severe disease relative to other variants.

Early data paint a mixed picture of Omicron’s evasion of vaccine-induced immunity. The UK Health Security Agency recently summed up its view. “Early estimates of vaccine effectiveness (VE) against symptomatic infection find a significantly lower VE [against] Omicron infection compared to Delta infection. Nevertheless, a moderate to high [VE] of 70 to 75 percent is seen in the early period after a booster dose.”

There is still much more to learn – antibody titers are an imperfect metric of immune protection, and major manufacturers are yet to release similar information. The response to Omicron may include both accelerating the rollout of booster doses of existing vaccines and developing new formulations better targeted to this variant. Companies have indicated that modified or new vaccines could be available in a few months, though the scale and global availability are unclear.

Regarding evasion of natural immunity, a preprint article from South Africa suggests a significantly higher chance of reinfection by Omicron relative to Delta or Beta. Both the pace of case growth and the rapidly increasing share of Omicron among samples sequenced suggest that through a combination of greater infectiousness and immune evasion, Omicron is spreading very quickly. If the experience of South Africa were to be repeated elsewhere, we could see a continued rapid increase in the number of Covid-19 cases as Omicron is established.

The question of disease severity is more complicated. Several clinicians in South Africa have noted the apparently mild presentation of Omicron cases. Further, the European Centre for Disease Prevention and Control (ECDC) noted on December 12, 2021, that 776 cases were within its remit and all cases for which there is available information on severity were either asymptomatic or mild. There have been no Omicron-related deaths reported thus far. On the other hand, ECDC also notes that it is too early to draw definitive conclusions on disease severity. The United Kingdom reported its first Omicron-related death on December 13, 2021, and some reports from South Africa suggest a potentially higher rate of hospitalization among young children than seen in previous waves of Covid-19.

Each of these observed trends may change as sample sizes increase, confounding factors are considered, and the clinical course of disease plays out over time. The answers, when they arrive, will have important consequences for the months ahead. Given the uncertainty, we have built a set of scenarios describing potential outcomes measured by hospitalization rate. They are indexed on the recent Delta wave and show whether various potential combinations of infectiousness, immune evasion, and clinical severity are likely to lead to a higher or lower rate of Covid-19-related hospitalization.

Evidence so far suggests that the Omicron variant, relative to Delta, is likely to be more infectious, show more immune evasion, and be less severe, on average. In the base case (25 percent more infectious; 25 percent greater immune evasion; 25 percent less severe disease), the Covid-19-related hospitalization rate could peak significantly higher in the next six months than in the past six. In the pessimistic scenarios, the peak number of hospitalizations for Covid-19 could be much higher in the next six months than in the past six months, whereas in the optimistic scenario, the number would be higher but similar to that seen in the second half of 2021, as waning immunity causes ongoing disease from a combination of the Delta and Omicron variants.

In the context of Omicron’s arrival and impending spread, three factors come to the forefront – the potential impact of new therapeutics in reducing hospitalizations and death, the criticality of boosters in the context of waning immunity, and clarity and consensus in public-health measures.

The clinical management of Covid-19 has come a long way since the early days of the pandemic. The availability of effective monoclonal antibodies, dexamethasone, and other treatments and the use of non-pharmacological interventions, such as proning, have meaningfully increased the chances of survival for those with access to high-quality healthcare. Nevertheless, recent results from Merck-Ridgeback Biotherapeutics and Pfizer on their oral drugs molnupiravir and PAXLOVID, respectively (two antivirals, with different mechanisms of action) represent a material advancement and increase the chance that the impact of the Omicron variant can be controlled. In its final study, Pfizer reported that PAXLOVID reduced the risk of hospitalization or death by about 89 percent for high-risk patients, and about 70 percent for standard-risk patients.

Oral therapeutics that significantly reduce the chance of progression to severe disease after symptom onset may enable a higher fraction of cases to be managed as outpatients. Such therapies are also easier to administer in lower-resourced regions than injected or infused treatments are. Further, manufacturing small molecules rapidly is faster than the process for monoclonal antibodies. The initial evidence indicates that the efficacy of these therapies is unlikely to be reduced by the mutations present in the Omicron variant.

A number of questions and caveats remain. Data are not yet available on the drugs’ efficacy in vaccinated individuals. Drugs are more likely to be effective if taken within five days of symptom onset, requiring an efficient pathway from diagnosis to prescription and distribution. And some data inconsistencies have emerged – for example, it is unclear why molnupiravir’s efficacy in an interim analysis dropped in the final readout.

Other questions relate to the impact of the new therapeutics in blunting an Omicron-driven wave of disease. Can healthcare systems diagnose Covid-19 and distribute therapeutics fast enough for them to be effective? Will oral therapeutics be available quickly enough to blunt a potential Omicron surge in December 2021 and January 2022? How will drug–drug interactions with ritonavir be managed for PAXLOVID use? Can mutagenicity concerns in pregnant women for molnupiravir be managed to ensure patient safety while maximizing effective use of the drug? What role will antibody treatments play?

The decline in the efficacy of Covid-19 vaccines over time and the benefits of booster doses have become much better understood over the past three months. While an initial course of all WHO-approved vaccines continues to provide strong protection against severe illness and death, the rate of breakthrough cases increases meaningfully as time passes, indicating that protection declines with time. For example, a July 2021 study of the Pfizer–BioNTech vaccine in Israel showed that in every age group studied, those who had been vaccinated by January 2021 were more likely to experience breakthrough infection than those who completed their initial course of vaccination two months later were. This general point appears to be especially true for the Omicron variant.

Evidence has also accumulated steadily about the benefit of booster doses, leading more countries to expand and accelerate their rollout. On October 21, 2021, Pfizer–BioNTech announced results from a randomized controlled trial of third dose of its Covid-19 vaccine; protection was restored to the levels seen in earlier trials after the second dose. More recent data, as previously described, highlight the benefits of booster doses in protecting against the Omicron variant.

WHO and others have raised important concerns about the appropriateness of high-income countries offering booster doses of Covid-19 vaccines while so many in the world have not received initial vaccination, but the benefits of a booster dose to an individual patient are increasingly clear. The ongoing Delta-driven wave of cases in Europe has led a number of countries to accelerate their booster-dose rollout, with some discussing the timing of potential additional doses.

As countries transition over time to managing Covid-19 as an endemic disease, the world may reach a long-term state of disease prevention similar to that seen with the flu, with annual or twice-yearly booster doses. In the short term, an accelerated rollout of booster doses of Covid-19 vaccines is likely to be one of the best protections against an Omicron-fueled wave of the disease.

Even before the emergence of Omicron, the past four months have seen the continued evolution of the public response to Covid-19. Debates have continued about the role of vaccine mandates, the use of vaccine passports, testing requirements, masks and mask mandates, and restrictions on gatherings. Societies are trying to find a new consensus through this transition, with some maintaining minimal public-health restrictions in the face of rising case counts and others reinstating more stringent measures. The emergence of Omicron led to tighter rules around travel in many countries, with some, such as England, also restricting domestic travel. Achieving some degree of consensus on public-health measures will likely be an important step toward controlling an Omicron-driven wave of disease.

The writing on the wall is clear. With Omicron, there’s no way really to escape this virus. The coronavirus will be with us forever, becoming a regional and endemic sickness every year. Either the whole world will be vaccinated or have been infected.