Omicron Variant: A Superspreader with Low Severity?
CDC reports breakthrough infections in vaccinated, even some boosted people
While the emerging omicron variant of COVID-19 is “blowing through” previously infected and vaccinated people in South Africa, there are early indications that the highly mutated virus will cause less severe disease. Of the first 43 cases in the United States, one was hospitalized for two days and none died, the Centers for Disease Control and Prevention (CDC) reported.1
A troubling finding in the same report suggests, as reported in South Africa, that the new variant will cause breakthrough infections in those fully vaccinated. Among the 43 cases, 34 (79%) occurred in those who had completed a primary series of COVID-19 vaccine. Fourteen of those 34 received an additional booster dose, although five had received it just recently and likely had not gained its immune benefits. Removing those, that means nine (21%) of the first 43 cases in the United States were fully immunized and boosted individuals. In addition, six people infected had a documented previous SARS-CoV-2 infection.
“Over half were between the ages of 18 and 39 [years] and one-third reported international travel before they were diagnosed,” said CDC Director Rochelle Walensky, MD, at a Dec. 10, 2021, White House press conference. “In reported cases so far, most people experienced only mild symptoms, which is what we would expect from a group of fully vaccinated individuals.”
The most commonly reported symptoms were cough, fatigue, and congestion or runny nose, the CDC reported. The breakthrough infections certainly are a concern, and the CDC report included this ominous note: “Even if most infections are mild, a highly transmissible variant could result in enough cases to overwhelm health systems.”
Certainly, the evidence emerging from South Africa suggests that the “highly transmissible” criteria are being met there, since estimates are that omicron is spreading roughly twice as fast as the delta variant.
The omicron outbreak in the Tshwane District of the Gauteng Province in South Africa is increasing rapidly. With the new variant first identified in the region in mid-November 2021, investigators reported about 42,000 cases in the province as of Dec. 3, 2021. Overall, the average number of daily cases in South Africa has increased from 350 on Nov. 1, 2021, to 13,500 on Dec. 8, with Omicron suspected as the main reason. Despite the surge, the perception that this is a milder version of the virus is reinforced by early reports from South Africa, which, it should be emphasized, represent only the first two weeks of the outbreak. “The main observation that we have made over the last two weeks is that the majority of patients in the COVID wards have not been oxygen-dependent,” the researchers reported.2 “SARS-CoV-2 has been an incidental finding in patients [who] were admitted to the hospital for an-other medical, surgical, or obstetric reason.”
In the United Kingdom, where public health officials project omicron will overtake delta as the predominate SARS-CoV-2 variant (> 50%) by mid-December 2021, there also was this finding: “[Omicron] continues to grow rapidly in all regions of England … None of the cases to date is known to have been hospitalized or died.”3
However, some are cautioning of the typical lag time between initial infection and hospitalization or death, and there also is an open and recurrent question about how omicron is going to affect unvaccinated children. Some in South Africa — where children younger than 12 years of age are not vaccinated — are being hospitalized, but the question of severity of illness and whether the coronavirus caused the hospital stay were unresolved.
‘There are other ways this can go’
Although the unfolding level of transmission has heightened concerns, the reports of mild cases have given rise to the speculative hope that the SARS-CoV-2 virus has evolved to a less severe form that will supplant the delta variant globally, causing less serious infections and fewer deaths.
Roger Shapiro, MD, MPH, a professor of immunology and infectious diseases at Harvard University, tempered these expectations while conceding that the scenario is a familiar evolutionary pattern in viruses. Shapiro has conducted extensive research in Africa as chair of the Botswana-Harvard AIDS Institute Partnership (BHP).
“It is possible for viruses to mutate in a way that either makes them more severe or less severe,” he said at a Dec. 3, 2021, Harvard press conference. “It’s very often the case that viruses adapt to become less severe over time, but it is not always the case. Over this short term, it is really hard to predict what direction will be most beneficial to the virus survival, which is really all the virus is concerned about: surviving and replicating. It is certainly tempting to think that a more transmissible, but less severe, virus would be advantageous, but there are other ways this can go. We can’t hang too much on that optimism.”
When the outbreak began in South Africa, approximately 30% of people had been fully vaccinated and about 40% had prior clinical COVID-19 infection, he said.
“There is evidence emerging that people who either had prior COVID or have been vaccinated can get this new omicron variant fairly easily,” Shapiro said. “It is blowing right through prior exposure and reinfecting people. Prior variants have not shown that [ability] as much as this variant, and that is one of the most worrisome features. It really seems to be transmitting despite evidence in people of prior COVID or vaccination.”
This new variant was first detected on Nov. 11, 2021, by Sikhulile Moyo, PhD, MPH, director of the BHP laboratory in Gaborone, Botswana.
The level of mutation was so unusual that Moyo immediately reran all lab procedures to see if an error was made, he said at the press conference. There was not.
“There was some selection advantage that allowed this virus to spread, probably because of increased transmissibility rather than immune escape,” Moyo said. “This suggests that other arms of the immune system will kick in to help. It is still early, of course.”
Indeed, there are other aspects of the human immune system, such as the cellular immune response, that should help keep those vaccinated out of the hospital, Shapiro said.
“All exposures to the virus or to a booster prime our immune system and keep us safer by getting both humoral and our cellular responses maximized,” Shapiro said. “Even if this new variant can escape the humoral response, the antibody response — the cellular response — can kick in and limit the disease to something mild or moderate.”
The booster may provide important immune enhancement, since Pfizer reports it increases neutralizing antibody titers by 25-fold against the omicron variant, compared to two doses.
“Preliminary laboratory studies demonstrate that three doses of the Pfizer-BioNTech COVID-19 vaccine neutralize the omicron variant (B.1.1.529 lineage), while two doses show significantly reduced neutralization titers,” Pfizer said in a statement.4 “As 80% of epitopes in the spike protein recognized by CD8+ T cells are not affected by the mutations in the omicron variant, two doses may still induce protection against severe disease.”
Breakthrough infections were always expected because the vaccines do not have 100% efficacy. A recent report issued by Washington state public health officials shows that from Jan. 17 to Nov. 27, 2021, 80,902 SARS-CoV-2 vaccine breakthrough cases were identified in the state.
“Among breakthrough cases from this surveillance period, 806 have died of COVID-related illness,” the report states.5 “The age range of deceased cases was 32-103 years (median 79 years).”
That translates to a mortality rate of just under 1% in breakthrough infections in fully vaccinated people. The report also cited an 8% hospitalization rate among those with that data reported, which was about half of the total cases. Given its heightened transmissibility, it appears increasingly likely that breakthrough infections will become much more of an issue with omicron. In fact, riffing off the CDC’s prior description of a pandemic of the unvaccinated, some have dubbed this omicron wave the “pandemic of the vaccinated.”
Concerning Mutations
Pei-Yong Shi, PhD, a distinguished professor of molecular biology at the University of Texas Health Science Center in Galveston, has been closely studying the new variant mutations in his lab.
“Two factors of the mutations in omicron are concerning,” he says. “First is the sheer number — 30 to 40. It really depends on how you count them in the different isolates. The number [of mutations] is way larger than the previous variants, including delta, which has around the range of a dozen.”
The second concern is the nature of these individual mutations, he says.
“There are a lot of ‘old comers’ that have been analyzed in other variants,” Shi says. “Like the 484 mutation and the 501 mutation. We have done a lot of work on these and they have clearly been shown to invade neutralizing antibody activities, like in the case of the Beta [variant], also first identified in South Africa. The 501 mutation increases the spike protein binding affinity to the receptor human S2 [binding sites] by hundreds of folds. It is concerning that these old mutations are there, and then there are a lot of new ones, which we [have not seen]. That combination has a lot of scientific foundation to trigger concern.”
After confirming the first isolate, Moyo shared the sequencing data with colleagues in South Africa, who also found omicron in specimens dating back several weeks.
As of Dec. 10, 2021, 25 U.S. states had identified cases and dozens of other nations have reported the omicron variant. Some cases were linked to travel, but others had no such history, making the travel ban imposed by the United States and other countries less likely to be effective.
“Travel restrictions don’t work with respiratory viruses,” Carlos del Rio, MD, distinguished professor of infectious diseases at Emory University in Atlanta, said at a recent briefing held by the Infections Diseases Society of America (IDSA). “They have never worked. We saw this in the 2009 [influenza pandemic], and we see it again with COVID. But politicians love them, and they think they’re useful. They aren’t.”
However, del Rio stressed that testing travelers is scientifically sound and more testing in general is going to be needed.
“As an individual, when I travel on a plane, I test myself 24 to 48 hours before I travel and I test myself two to three days after I land,” he said. “I think it’s a very effective way of knowing if you’ve been exposed and then preventing transmission to others.”
After a slow start, genomic surveillance to detect different variants improved in 2021 in the United States. “Currently, about 5% to 7% of cases get genomic surveillance, but we need more testing, more genomic surveillance to be able to identify where these cases are,” del Rio said.
With the new variant now being identified globally, the travel bans to Africa by the United States and other nations will only exacerbate the problem in under-resourced countries, Moyo said.
“Look at how many continents, how many countries are reporting omicron right now,” he said. “This indicates that we are a global economy, a global village, and we should be responding in a similar way — with a global response.”
‘Vaccinate Africa’
Indeed, infectious disease clinicians and researchers in South Africa warn that the scarcity of COVID-19 vaccination in Africa and a large population of immune compromised human immunodeficiency virus (HIV) patients — 8 million of whom are not receiving antiretroviral treatment to fend off full-blown acquired immune deficiency syndrome — sets the stage for continued mutation and global spread of SARS-CoV-2.6
It should be emphasized that it has not been determined definitively how the highly mutated omicron variant arose, with some hypothesizing a reverse zoonosis — a reintroduction into an animal population, a period of mutation, and then transmission back to humans.
“There is some science suggesting this might be the case because we see some mutations that are also found in rodents,”says Mirella Salvatore, MD, an infectious disease professor at Weill Cornell Medicine in New York.7 “Everything is speculation [at this point], but that is a possibility. Another possibility certainly is that it replicated in an immune-compromised host. For example, flu can replicate for four or five months in an immune-compromised host. Also, in an area where there is a low vaccination rate and no surveillance, mutations can go undetected in an immunocompromised host.”
Indeed, the prevailing theory among many scientists is just that: Omicron arose after prolonged mutation in an immunocompromised patient.
“Immunocompromised people with COVID promote the mutation and amplification of the virus,” Shi says. “That is the opportunity for the virus to change — it is like some sort of incubator or a petri dish. The virus can grow easily without much pushback from immune protections.”
In that regard, the aforementioned South African researchers described a case in their country in which SARS-CoV-2 persisted more than six months in a patient with uncontrolled, advanced HIV.6
It would be of great global benefit if richer nations helped Africa prevent and treat COVID-19 and HIV simultaneously, they emphasized. A top priority in such an endeavor would be to “vaccinate Africa” for COVID-19.
“Over and above the ethical arguments to address vaccine nationalism and reduce deaths globally, the available data strongly indicate that vaccinating people in Africa will help to reduce transmission rates globally, limit the emergence of new variants and accelerate global control of the pandemic,” they said.
del Rio concurred with this line of thought at the IDSA briefing.
“It appears to be a virus that emerged in a single patient, likely somebody severely immunosuppressed, who could not clear the infection, and as the virus replicates in that individual it starts accumulating mutations,” he said. “I think it really emphasizes the importance of vaccinating the world. If a patient in South Africa was immunosuppressed, was not vaccinated, and this happened, that’s clearly a concern.”
REFERENCES
- CDC COVID-19 Response Team. SARS-CoV-2 B.1.1.529 (Omicron) variant — United States, December 1-8, 2021. MMWR Morb Mortal Wkly Rep 2021; Dec 10. doi: http://dx.doi.org/10.15585/mmwr.mm7050e1. [Online ahead of print].
- Abdullah F. Tshwane District omicron variant patient profile - early features. SAMRC. https://www.samrc.ac.za/news/tshwane-district-omicron-variant-patient-profile-early-features
- UK Health Security Agency. COVID-19 variants identified in the UK. Updated Dec. 13, 2021. https://www.gov.uk/government/news/covid-19-variants-identified-in-the-uk
- Pfizer. Pfizer and BioNTech provide update on omicron variant. Published Dec. 8, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-provide-update-omicron-variant
- Washington State Department of Health. SARS-CoV-2 vaccine breakthrough surveillance and case information. Published Dec. 8, 2021. https://www.doh.wa.gov/Portals/1/Documents/1600/coronavirus/data-tables/420-339-VaccineBreakthroughReport.pdf
- Msomi N, Lessells R, Mlisana K, de Oliveira T. Africa: Tackle HIV and COVID-19 together. Nature 2021; 600:33-36.
- Branswell H. Some experts suggest omicron variant may have evolved in an animal host. Stat. Published Dec. 2, 2021. https://www.statnews.com/2021/12/02/some-experts-suggest-omicron-variant-may-have-evolved-in-an-animal-host/
While the emerging omicron variant of COVID-19 is “blowing through” previously infected and vaccinated people in South Africa, preliminary evidence indicates the highly mutated virus will cause less severe disease.
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