COVID is back. How dangerous is the new wave and are new vaccinations necessary?

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What is going on?

After a brief lull, there has been a steady increase in new cases of coronavirus around the world. Since mid-June, countries have regularly reported an increasing number of new cases - and this despite markedly lower testing volumes. The so-called test positivity rate, that is, the ratio of positive results to the total number of tests performed, has also increased. In New York City, for example, the positive rate was 15 percent in mid-July, the last time it was that high was in January during the first omicron wave. The higher the positive rate, the more people get sick - even if we don't catch all of them by testing.

Hospitalizations of people with coronavirus infection are also on the rise - in the U.S., for example, the number has doubled since the beginning of July, and the number of people admitted with covid has increased by 22 percent. It is not uncommon for patients who have been admitted to hospitals for other reasons to be diagnosed. This is another indirect sign that the virus has become widespread. Meanwhile, the number of deaths worldwide has remained constant, although South Africa, for example, has seen a 23% increase in deaths from the coronavirus and its effects, and there has been a 78% increase in the Middle East.

The new rise in incidence has been caused by two close sub-variants of omicron BA.4 and BA.5. They differ in only a few mutations, so they are usually written down together, BA.4/5, although BA.4 is increasingly rare and the main culprit of the new wave - which is undoubtedly happening - is the BA.5 variant The BA.4/5 pair became prominent among other versions of the coronavirus in April 2022, and by early summer overtook all competitors in most regions of the planet, including the other two omicron variants, BA.1 and BA.2, from which BA.4 and BA.5 once branched off.

BA.4/5 are evasive variants. This means that the mutations that occurred in their spike protein changed it so much that antibodies developed after encountering previous varieties of coronavirus antigens - whether after infection or vaccination – can no longer recognize it. Technically, this means that both those vaccinated and those who have contracted other variants of SARS-CoV-2, including previous versions of omicron, are highly likely to contract BA.4/5. However, the risk of a severe course of infection with BA.4/5 for people whose immune systems have already encountered the coronavirus appears to be lower because it is not only related to antibodies but also to T-cells, and they are less sensitive to SARS-CoV-2 mutations.

Additional capacity to infect people with BA.5 may emerge from changes that help that variant evade not only antibodies but also innate defense systems. Such a hypothesis has been suggested by the authors of a recent study. If this assumption is confirmed, we can predict that BA.4/5 will spread even faster than its predecessors of the omicron “lineage”.

Understanding whether the new omicron variants became more or less pathogenic is very difficult. During the first coronavirus waves, most of the world's population had no immunity against the disease, but now the proportion of those who have never encountered coronavirus antigens is vanishingly small: the epidemic has reached even the most remote populations, such as the Indians in the Amazon Valley or the Inuit and other indigenous peoples of Canada. Nevertheless, preliminary laboratory data indicate that the BA.4/5 variants cause more damage to lung cells than the earlier versions of omicron, but apparently less than the delta variant. This indirectly suggests a greater pathogenicity of those variants compared to the BA.1 and BA.2 variants, but we are yet to obtain sufficient clinical data to confirm or refute this hypothesis.

However, the symptoms of the early stages of the disease have not changed much: those infected with the BA.4/5 versions complain of weakness, headache, sneezing, runny nose and sore throat. According to data collected by the symptom-tracking app Zoe, only one-third of those who get sick have a fever, and a debilitating cough occurs mostly in the unvaccinated. Odor loss also occurs, but how often is still hard to say. So far, each new dominant variant has caused this symptom less frequently than the previous ones, and for the first wave of omicron associated with variants BA.1 and BA.2, it was not at all characteristic: the frequency of anosmia was only 17% of what it had been at the beginning of the pandemic.

How dangerous is the new wave?

So far, experts avoid making any predictions, because the wave is just emerging and the dynamics of hospitalizations in intensive care units and deaths is unclear. However, we know from experience with the initial varieties of omicron, that the less pathogenic (under the current circumstances it doesn’t matter whether in general or in respect of the immune population) but more contagious strains are capable of killing approximately the same number of people. The absolute number of deaths during the waves caused by delta and omicron variants was the same, although many more people were infected in the omicron wave.

If BA.4/5, through evading antibodies, infects a large number of people, the resulting mortality rate could be significant, even though infected young people without comorbidities rarely develop a severe course. For people at risk, the mass spread of the new variant of the virus can be very dangerous, as they are more likely to suffer serious consequences if infected, even if they have received all the recommended vaccinations. On the other hand, the most vulnerable patients died in the first waves of coronavirus, which were relatively recent, so the peak deaths may be lower than those seen before.

Another significant health and quality-of-life consequence of coronavirus infection is what is known as long-covid. This term is used in situations where, after the acute phase of the disease has ended, the results of tests for SARS-CoV-2 have long since come back negative, but the person still has some form of symptoms. Typical signs of long-CoV include memory and attention deficits and other neurological disorders, inability to tolerate even minimal physical exertion, shortness of breath, constant fatigue, and more. The severity of symptoms varies markedly across the population, but some people with this disorder cannot lead fulfilling lives and work.

The causes of long-covid are not well understood - and thus there are no relevant ways to combat it - but most experts attribute it to long-term immune system dysfunction triggered by the virus. The incidence of this disorder during the reign of the different variants of SARS-CoV-2 was uneven; for example, after the delta-caused wave, about 11% of survivors suffered from long-covid, while after the first wave of omicron, only 4.5% suffered from long-covid. In the next few months, we will be able to tell the frequency of the long-covid symptoms in survivors of the disease caused by BA.4/5.

Should new vaccinations be performed and existing vaccines modified?

Existing vaccines today, especially those from the mRNA group of drugs, have been extremely effective in preventing infection with early versions of the coronavirus and the severe course of the disease. However, omicron has changed a great deal from its predecessors, and the antibodies developed after vaccination are no longer able to prevent its entry into cells. In other words, those vaccinated (and those who have become ill) can become infected again.

The obvious solution to this problem seems to be to modify the vaccines so that they stimulate the production of antibodies that recognize the new varieties of SARS-CoV-2. And pharma companies have already done that: the mRNA vaccine manufacturers Pfizer/BioNTech and Moderna, as well as the creators of Russia's Sputnik, have developed new versions of omicron-modified vaccines. Moreover, an expert panel at the FDA, the U.S. regulator, recommended on June 28 that the vaccine formulation be updated to include components that stimulate the production of antibodies to the omicron variant.

However, it is not certain that such a solution will drastically reduce the number of new infections. Preliminary trials and tests show that booster two-component vaccines stimulating the production of antibodies to both the original strain and the omicron yield only a small increase in neutralizing (the most effective) antibodies compared to the existing drugs – nearly by a factor of two. Whether such a difference in antibody count has a clinical effect is questionable, but most likely it has not.

The unexpectedly low efficacy of the new versions of the vaccines may be at least partly related to the so-called antigenic sin - the tendency of the immune system to utilize the “immunological memory” created during the first encounter with the pathogen in new encounters. If this is the case, we can expect that for those vaccinated and those who have had previous variants of the coronavirus, modification of the existing vaccines will not produce a radical improvement in protection.

Besides, mass production of modified vaccines will not begin until the fall, and although by then it is likely that BA.5 will still be the main strain in the world, it is impossible to predict how soon it will be replaced by another variant. The coronavirus has demonstrated an unusually high capacity for mutation - for example, another omicron variant, BA.2.75, is already gaining momentum in India - and there is a possibility that new two-component vaccines will be obsolete in a few months, too.

That said, existing vaccines still protect people well against the severe course, especially if the booster has been administered recently. With this in mind, medical regulators in the U.S. and Europe have already recommended that the elderly get a second booster with mRNA drugs, and there are discussions in the U.S. about extending that recommendation to younger people as well. Nevertheless, it is likely that both the U.S. and Europe will approve new two-component vaccines.

In Russia, the only vaccine for which there is evidence of efficacy is Sputnik, aka Gam-COVID-Vac. However, until now, its developers have not published the results of the studies showing how effective the drug remains against BA.4/5. The latest paper on the preprint website is devoted to the immunological efficacy of Sputnik against the first omicron varieties, that is, not to data based on actual diseases but on estimated antibody count in the blood of vaccinated patients. Anatoly Alshtein, a senior researcher at the Gamaleya Research Center, where Sputnik had been developed, said in an interview that the vaccine was not as effective against the delta variant and even less effective against omicron. However, Alstein was not involved in the creation and efficacy studies of Sputnik, so we have no reliable data on the extent to which immunization with those vaccines protects against BA.4/5 infection and the severe course caused by those variants.

What about medicines?

In contrast to the first waves of SARS-CoV-2, today we have several groups of drugs that prevent the severe course or reduce its effects. The first group includes primarily paxlovid (nirmatrelvir 300 mg per dose + ritonavir 150 mg per dose) and some monoclonal antibodies. Paxlovid blocks the action of the virus’s main protease, which the virus needs to cut the protein “blanks” synthesized from the genome into individual proteins.

Paxlovid, developed by Pfizer, is not available in Russia, but two of its analogues, Skyvir and mirabivir, were registered there in spring. At the end of February it was reported that phases I and II of nirmatrelvir/ritonavir clinical trials would be conducted in the country, however nothing was reported about the results of these trials prior to the registration of both drugs.

Monoclonal antibodies are lab-created analogs of human antibodies that attack the most vulnerable sites of the viral particle. They are extremely sensitive to spike-protein mutations, so a different drug should be used in each wave for maximum efficacy. Almost all existing monoclonal antibodies are no longer effective against BA.4/5. Evusheld from AstraZeneca retains relative efficacy, although its neutralizing ability has dropped 8-fold compared to BA.2, and so do the antibodies bebtelovimab and cilgavimab.

If the patient's symptoms become severe, doctors use various agents to reduce hyperinflammation - the pathological reaction of the immune system to the invasion of the virus, which leads to a worsening of the medical condition. Over two years of patient observation and clinical trials, scientists and physicians have developed effective use strategies - but not all countries base their treatment procedures on internationally recognized guidelines. Hence the disproportionately high excess mortality rates in some countries.