Tons of snippets today

Tons of snippets today

The UKHSA's data yesterday suggests that although it appears the risk of being hospitalised by Omicron is comparatively low, the agency added that there is a higher chance of being infected in the first place, as Omicron is more transmissible and more likely to evade immunity from current vaccines. What are the key findings from the UKHSA's study?

  • People with Omicron are up to 70% less likely to be admitted to hospital than those with Delta
  • Those with the new strain are up to to 45% less likely to go to A&E
  • Most Omicron infections are among those aged 20 to 40 years old
  • The new strain is believed to be infecting more people who have previously had Covid - almost 10% of people with Omicron have had it before
  • Vaccination gives less protection against Omicron than Delta, but depending on the type of vaccine given for the first two doses, the booster jab adds 15% to 25% more protection against symptomatic infection with Omicron
  • Protection against Omicron starts to wane 10 weeks after booster vaccination:

The reduction in the infection fatality rate (IFR) is probably even greater. Infections in London are peaking, yet ICU occupancy is stable. Meanwhile, South Africa’s Omicron wave is receding, while deaths remain at negligible levels. Omicron will probably peak in the UK in late December and in the United States and continental Europe in early January. European governments might introduce a few light restrictions in the lead-up to New Year’s Day, but the impact will be minimal as one can now expect any tightening to last no more than a few weeks. In well-vaccinated areas, Omicron will more closely resemble a seasonal flu than a prior wave of COVID-19. Fourth doses (“second boosters”) will be coming in 2022.

Other points:

  • Daily new Omicron infections are rising in the UK as a whole, but cases in London appear to be peaking.
  • The number of COVID-19 hospital patients in London is rising but remains far below levels at similar points in previous waves. ICU bed occupancy in the city remains stable (see chart).
  • Hospitalisations will keep rising in the UK and Europe in the coming weeks, but pressure on ICUs seems likely to peak at far lower levels than in previous waves.
  • A Scottish study found that Omicron is two-thirds less likely to lead to hospitalisation. It also found that boosters provide strong protection against severe disease from Omicron:

https://www.research.ed.ac.uk/en/publications/severity-of-omicron-variant-of-concern-and-vaccine-effectiveness-

  • Another UK study concluded that Omicron infections are 40% less likely than Delta to result in hospital stays of one or more days:

https://www.imperial.ac.uk/media/imperial-college/medicine/mrc-gida/2021-12-22-COVID19-Report-50.pdf

  • Further, a South African paper found that Omicron infection is associated with a much lower risk of hospitalisation compared to Delta infection.
  • The South African data are still not good enough to assess how Omicron affects older and unhealthier individuals. The confidence intervals are so wide as to be practically useless.
  • If Omicron is as virulent as Delta in these populations, it could still cause a significant wave of deaths, particularly in poorly vaccinated pockets of developed markets like the American South.
  • Still, deaths data out of South Africa remain extremely encouraging. Nationwide, cases peaked about a week ago, yet South African deaths are 85% below their Delta wave peak.
  • The UK is finding very few Omicron-related infections amongst elderly age groups, likely because most of this demographic has received boosters.
  • In the coming days, more European countries may impose additional restrictions, but these will last for a couple of weeks at most.
  • Cases are rising in France and Italy. The Netherlands, which is still in the tail end of its Delta wave, reintroduced a four-week full lockdown late last week.
  • This week, Germany, Finland, and Portugal introduced curfews and restrictions on social mixing.
  • Infections are also rising in the U.S., where Omicron is now dominant.
  • Southern states hospitalisations are also trending up, but at a much slower rate than in prior waves.
  • The biggest waves of hospitalisations and deaths will be clustered in rural areas and Southern and Midwestern states where vaccination rates are below average, restrictions are politically off the table and consumer behaviour is unlikely to adapt.
  • Entering 2022, it is China that is the most vulnerable major economy to COVID.
  • On December 22, a full lockdown was introduced in Xi’an, a city of 13 million people, in response to a small Delta outbreak.
  • Tianjin, a port city, locked down in mid-December after an Omicron case was discovered there.
  • Omicron’s ultra-high transmissibility, vaccine-evading capability, and shorter incubation period pose a major challenge to the Chinese government’s “dynamic zero COVID” strategy.
  • Serology studies show Chinese vaccines do not work against Omicron, even as boosters:
  • https://www.hku.hk/press/press-releases/detail/23804.html
  • Sinovac recently issued a strident rebuttal, stating without evidence that its formulation is 97% effective against Omicron. This week, it had to backtrack.
  • The Chinese government will use Omicron as an excuse to keep its borders shut to foreigners into 2023 and possibly beyond.
  • Meanwhile, Israel this week authorized a second booster (fourth dose) for over-60s and healthcare workers who are at least four months past their third shot.
  • I think this will become standard in most Western countries and in Asia in 2022, with uptake levels in the United States falling far behind the rest of the OECD.
  • On Monday, Moderna released data showing that its booster leads to a 37-fold increase in neutralizing antibody levels.

By end-January, European governments will wind down any additional restrictions they may impose in the coming days. Yet Omicron will still have important long-term geopolitical and macroeconomic effects, not least because it provides a convenient excuse for China to keep its borders tightly shut through 2022 and beyond. Updated vaccine effectiveness analysis shows mRNA boosters beginning to wane from one month (week 5-9) for Omicron, and as low as 30-50% effective from 10 weeks post-booster:

But, some may say the world is looking better now as per this:

The FDA has approved Merck’s pill too. But, a little over a week after French regulators decided against authorizing Merck’s Covid-19 antiviral pill, the country has cancelled its order, according to multiple reports. A Merck spokesperson told Reuters that France’s planned purchase didn’t take place after the country’s health authority rejected the pill over growing concerns about efficacy and the impact of the Omicron variant. The country had pre-ordered enough doses to treat 50,000 patients. The FDA authorized the Ridgeback Biotherapeutics-partnered drug, called molnupiravir, on Thursday. The US could have about 400,000 courses available in the next few days, and by the end of January, the US government expects to have about 3 million courses, which is the entire order that the US made.

Merck had originally said molnupiravir, reduced the risk of death and hospitalisations by 50%. Then in late November, the company came back with updated data that suggested molnupiravir only cut the risk by about 30% compared to placebo. Last month, the FDA’s Antimicrobial Drugs Advisory Committee voted 13-10 in favour of the pill’s benefits outweigh the risks for adults within 5 days of developing Covid symptoms. This week, US regulators signed off on Pfizer’s Covid-19 pills, made up of nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use. Pfizer’s pill, known as Paxlovid, proved to reduce the relative risk of hospitalisation or death by 89% (within three days of symptom onset) and 88% (within five days of symptom onset) compared to placebo in a trial of more than 2,000 people.

This is currently UK cases confirmed using Taqpath PCR assay. S-gene target failure (SGTF) in purple is a surrogate for Omicron:

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1043466/20211222_OS_Daily_Omicron_Overview.pdf

Hospitalisations in Gauteng:

Time series of primary series/booster vaccinations (top), new COVID cases (middle) and current hospitalisations due to COVID (bottom) in the US:

I note Novovax are making an Omicron specific shot, which is ‘kind of’ strange as their trials were done pre-Delta. “ Two-dose primary regimen of NVX-CoV2373 demonstrated cross-reactive immune responses against Omicron (B.1.1.529) and other variants:

  • Third dose produced increased immune responses comparable to or exceeding levels associated with protection in Phase 3 clinical trials, with a 9.3-fold IgG rise and a 19.9-fold ACE2 inhibition increase after booster dose
  • Immune responses in adolescents were 2- to 4-fold higher than adults against broad array of variants of interest and variants of concern
  • Development of Omicron-specific vaccine on track for initiation of GMP manufacturing in early January.

With EU and WHO approvals in hand, and more EUA authorisations coming, a key question has been how does NVAX’s vaccine as two-dose and three-dose regimens fare vs. Omicron and whether the lack of that data would hamper the rollout of NVAX’s vaccine. The two-dose regimen shows nAbs activity against Omicron, albeit ~4 fold reduced, and the booster dose increases nAbs to levels seen with the primary series vaccine against WT virus, suggesting the potential for a high level of protection.

Snippets:

Researchers asked what factors are associated with adverse effects after COVID-19 vaccination? In an online cohort study including 19,586 adults who received a COVID-19 vaccination, the factors most strongly associated with adverse effects were full vaccination dose, brand of vaccine, younger age, female sex, and having had COVID-19 before vaccination. Allergic reaction or anaphylaxis was reported in 0.3% of participants after partial vaccination and 0.2% of participants after full vaccination. These findings suggest that some individuals experience more adverse effects after COVID-19 vaccination, but serious adverse effects are rare:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787361

In a huge US study, vaccination status was associated with lower SARS-CoV-2 infection rates. Persons who received mRNA vaccines (BNT162b2 or mRNA-1273) had the lowest incidence rate at every point of the observational time, and unvaccinated persons in this cohort had the highest rate. Unvaccinated persons had 412%, 287%, and 159% more infections that people who received mRNA-1273, BNT162b2, or JNJ-78436735 vaccines, respectively. The observed incidence rate during the study period was 24.8% (unvaccinated), 15.6% (JNJ-78436735), 8.6% (BNT162b2), and 6.0% (mRNA-1273). The magnitude of SARS-CoV-2 risk for unvaccinated persons increased even more in July and August, parallel with the increasing prevalence of the Delta variant in the US. When restricted to fully vaccinated persons, the trend was nearly identical:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787363

COVID-19 mRNA vaccine immunogenicity and effectiveness are well established in adolescents. However, the effect of vaccination on multisystem inflammatory syndrome in children (MIS-C), a severe complication associated with SARS-CoV-2, has not yet been described. Summer 2021 in France was marked by both a fourth wave of COVID-19 cases due to the Delta variant, with a peak in August 2021, and by the recommendation of the French Public Health Agency to vaccinate children 12 years and older. Researchers estimated the risk of MIS-C among adolescents by COVID-19 vaccination status during September 2021 and October 2021. They found most adolescents with MIS-C for whom vaccination was indicated in France had not been vaccinated. These results suggest that COVID-19 mRNA vaccination was associated with a lower incidence of MIS-C in adolescents. The median of 25 days between single vaccine injection and MIS-C onset compared with a mean 28-day delay between SARS-CoV-2 infection and MIS-C onset suggests that, in most cases, SARS-CoV-2 infection occurred before or shortly after the vaccine injection, when immune response was incomplete. The absence of MIS-C cases in fully vaccinated children prevented calculation of an HR for this group, but suggests that 2 doses are warranted for efficient protection:

https://jamanetwork.com/journals/jama/fullarticle/2787495

Identifying which children and young people (CYP) are most vulnerable to serious infection due to SARS-CoV-2 is important to guide protective interventions. To address this question, a group used data for all hospitalisations in England among 0–17 year olds from 1 February 2019 to 31 January 2021. They examined how sociodemographic factors and comorbidities might be risk factors for pediatric intensive care unit (PICU) admission among hospitalisations due to the following causes: COVID-19 and pediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the first pandemic year (2020–2021); hospitalisations due to all other non-traumatic causes in 2020–2021; hospitalisations due to all non-traumatic causes in 2019–2020; and hospitalisations due to influenza in 2019–2020. Risk of PICU admission and death from COVID-19 or PIMS-TS in CYP was very low. They identified 6,338 hospitalisations with COVID-19, of which 259 were admitted to a PICU and eight CYP died. They identified 712 hospitalisations with PIMS-TS, of which 312 were admitted to a PICU and fewer than five CYP died. Hospitalisations with COVID-19 and PIMS-TS were more common among males, older CYP, those from socioeconomically deprived neighbourhoods and those who were of non-White ethnicity (Black, Asian, Mixed or Other). The odds of PICU admission were increased in CYP younger than 1 month old and decreased among 15–17 year olds compared to 1–4 year olds with COVID-19; increased in older CYP and females with PIMS-TS; and increased for Black compared to White ethnicity in patients with COVID-19 and PIMS-TS. Odds of PICU admission in COVID-19 were increased for CYP with comorbidities and highest for CYP with multiple medical problems. Increases in odds of PICU admission associated with different comorbidities in COVID-19 showed a similar pattern to other causes of hospitalisation examined and, thus, likely reflect background vulnerabilities. These findings identify distinct risk factors associated with PICU admission among CYP with COVID-19 or PIMS-TS that might aid treatment and prevention strategies:

They found that very few CYP admitted to hospital in England due to COVID-19 or PIMS-TS went on to develop severe disease or die. Of the 12.02 million 0–17 year olds in England during 2020, 1 in 2,062 (n = 5,830) was admitted to hospital due to COVID-19, and 1 in 47,903 (n = 251) was admitted to a PICU. This represented only 1.3% of all secondary care admissions in the pandemic year and less than 5% of non-traumatic emergency PICU admissions. Eight of these CYP died within 28 d of admission to hospital. For PIMS-TS, 1 in 17,425 (n = 690) of CYP in England was admitted to hospital; 1 in 38,911 (n = 309) was admitted to a PICU; and fewer than five CYP died. This likely represents all PIMS-TS cases nationally over the study period, as the vast majority will have required hospitalisation:

https://www.nature.com/articles/s41591-021-01627-9

What is the risk of acute respiratory distress syndrome (ARDS) and death in patients with COVID-19 with metabolic syndrome? In this cohort study including 46,441 patients hospitalized for COVID-19, metabolic syndrome was associated with significantly increased odds of ARDS and death. With each metabolic syndrome criterion added from 1 to 4 criteria, the risk of ARDS significantly increased in an additive fashion. These findings suggest that metabolic syndrome and its associated comorbidities were critical risk factors associated with COVID-19–related ARDS and death:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787394

How have the mental health and well-being of older adults in England changed during the COVID-19 pandemic compared with pre-pandemic levels? This cohort study including 5146 older adults participating in the English Longitudinal Study of Ageing found that levels of depression, loneliness, and poor quality of life increased significantly during June and July 2020 compared with pre-pandemic levels and continued to deteriorate during the second national lockdown in November and December 2020, with further increases in anxiety symptoms from June and July 2020 to November and December 2020. Inequalities in experiences of mental ill health during the COVID-19 pandemic were evident, with women, individuals living alone, and those with less wealth being particularly vulnerable. Older individuals did not adapt well to the new psychosocial stressors introduced by the pandemic; policies should be in place for the immediate provision of targeted psychological interventions to support older people, and access to digital mental health services should be improved:

The results provided clear evidence for an overall deterioration in all mental health outcomes, which persisted throughout the course of the COVID-19 pandemic in 2020. Levels of depression, poor quality of life, and loneliness increased significantly during June and July 2020 and again in November and December 2020 compared with pre–COVID-19 pandemic levels. The largest changes were observed for depression (β range, 0.26 to 0.41), followed by poor quality of life (β range, 0.15 to 0.24), and loneliness (β range, 0.08 to 0.13). They also found a significant increase in the levels of anxiety during the COVID-19 pandemic (β = 0.06; 95% CI, 0.01-0.10). Furthermore, they showed that changes in mental health varied across distinct sociodemographic groups. Deterioration of mental health was greater in women than in men across all outcomes. Participants with less wealth had lower levels of mental health than those in the highest wealth group, before and during the COVID-19 pandemic. Nevertheless, people with higher wealth experienced more negative changes in quality of life and loneliness throughout the COVID-19 pandemic. Mean ratings of loneliness increased among people who did not have a partner and were living alone:

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2787196

Whether the use of remdesivir in symptomatic, non-hospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalisation is uncertain. A team conducted a randomized, double-blind, placebo-controlled trial involving non-hospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. A total of 562 patients who underwent randomisation and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19–related hospitalisation or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. Among non-hospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalisation or death than placebo:

https://www.nejm.org/doi/full/10.1056/NEJMoa2116846?

Remdesivir, a nucleotide analogue prodrug that inhibits the viral RNA-dependent RNA polymerase, was approved by the FDA in October 2020 for adults and select pediatric patients with severe Covid-19 who require hospitalisation. In a randomized, double-blind, placebo-controlled trial, it was shown to reduce the median time to clinical improvement from 15 days to 10 days, with a larger benefit seen when treatment was started earlier in the disease course. Remdesivir has since been evaluated in other trials, with mixed results, as the use of systemic glucocorticoids has increased. In the most recent DisCoVeRy trial, which showed no clinical benefit of treatment with remdesivir, the median time from symptom onset to initiation of treatment was 9 days, long after the time of the peak viral load in most patients, reinforcing the theory that remdesivir is more likely to have a clinically meaningful benefit before hospitalisation than later in the disease course.

This trial aimed to evaluate early outpatient remdesivir treatment to prevent progression to severe Covid-19. Unvaccinated patients with confirmed SARS-CoV-2 infection and at least one risk factor for progression to severe disease who had onset of symptoms within 7 days before randomisation were assigned to receive a 3-day outpatient course of intravenous remdesivir or placebo. The percentage of patients who had a Covid-19–related hospitalisation was significantly lower in the remdesivir group than in the placebo group (0.7% vs. 5.3%; hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.59); these results equate to a difference of 47 fewer hospitalisations per 1000 infections, a clinically significant finding in an overwhelmed health care system. Notably, no deaths had occurred in either group by day 28. However, the change in viral load, determined with the use of nasopharyngeal swabs, from baseline to day 7 in the remdesivir group was similar to that in the placebo group.

Although the findings of this trial represent the most promising of any remdesivir study to date because of the timely administration of the medication, several practical limitations must be noted. First, the exclusion of vaccinated patients limits understanding of the utility or requirement of early antiviral therapy in vaccinated persons with breakthrough infections. Second, the lack of effect of remdesivir on SARS-CoV-2 viral loads reflects that the way in which this medication improves a patient’s clinical disease course is still uncertain. Although SARS-CoV-2 nasopharyngeal viral loads do not reliably predict treatment outcomes in Covid-19, in a randomized, controlled trial of remdesivir conducted in China, SARS-CoV-2 viral burden (as determined by means of quantitative polymerase-chain-reaction assay of specimens from both the upper and lower respiratory tracts) did not differ between patients in the remdesivir group and those in the control group. So the question arises of whether remdesivir would in fact reduce transmissibility in infected persons (an important consideration in outpatient therapeutics) as compared with monoclonal antibodies or new oral antiviral agents, which are both associated with a more rapid decline in viral burden than placebo. Evaluation of the effect of remdesivir on viable virus may be required to confirm the mechanism of observed clinical benefit. Finally, the primary challenge for implementing outpatient remdesivir treatment is the pragmatic difficulty of administrating a 3-day course of an intravenous agent. Access to and uptake of single-dose monoclonal antibodies have been challenging, a fact that does not bode well for a 3-day course of outpatient intravenous remdesivir. Although remdesivir administration requires less monitoring than monoclonal antibody administration, the majority of patients in this trial received remdesivir outside of their home or nursing facility, necessitating multiple health care interactions during the time the patients were acutely infected. Agents that could be administrated orally would be vastly easier to implement in the outpatient setting.

The findings of this trial reinforce the need for timely access to outpatient therapeutics and support the proof of concept for pursuing oral prodrugs of remdesivir’s active metabolite. Rapid emergence of variants with adaptive mutations in the spike protein can result in escape from vaccines and monoclonal antibodies, whereas antiviral agents, given the absence of variation in their viral target, are likely to maintain activity, reinforcing the value of antivirals such as remdesivir in curtailing the pandemic. If Covid-19 is here to stay, our focus on prevention through vaccines remains a priority, but therapeutic options to keep vulnerable patients out of the hospital are an important tool in the armamentarium.

https://www.nejm.org/doi/full/10.1056/NEJMe2118579

In March 2021, concerns were raised about an increased risk of thrombosis associated with thrombocytopenia among persons who had received their first dose of the ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccine. Between 5 and 30 days after vaccination, severe thrombosis developed in these patients, most of whom were previously fit and well. The thrombosis often occurred at unusual or multiple sites, in conjunction with thrombocytopenia, grossly elevated d-dimer levels, reduced fibrinogen levels, and the presence of anti–platelet factor 4 (PF4) antibodies. To determine the risk of a second Covid-19 vaccine dose in these patients with vaccine-induced immune thrombotic thrombocytopenia (VITT), the U.K. Health Security Agency (formerly Public Health England) identified the patients who had received a second vaccine dose and contacted the primary care physicians for follow-up. A total of 40 patients were identified as having confirmed (26 patients), probable (2 patients), or possible (12 patients) VITT, after receiving their first dose of ChAdOx1 nCoV-19. The patients ranged in age from 21 to 76 years, and 25 were women. Five of the patients had received a second dose of ChAdOx1 nCoV-19, 2 had received mRNA-1273 (Moderna), and 33 had received BNT162b2 (Pfizer–BioNTech).

None of the 40 patients had any relapse of symptoms or severe adverse reactions after receiving the second dose of vaccine, regardless of the vaccine received. Although the mechanism of VITT is still not known, the absence of relapse suggests that the phenomenon is not related to the immune response to the spike protein. This conclusion is consistent with that reported by others who showed that the anti-PF4 antibodies that are detected in patients with VITT do not interact with epitopes on the spike protein and appear to be independent of the spike antibody response. Furthermore, VITT is rarely, if at all, associated with vaccination with non–adenoviral vector vaccines, such as the messenger RNA (mRNA) vaccines. Patients with VITT should be advised to complete their Covid-19 vaccine course to improve protection. In this study, the majority of patients had received BNT162b2 as their second dose, with no adverse effects:

https://www.nejm.org/doi/full/10.1056/NEJMc2118507?

Residents of long-term care facilities are particularly vulnerable. To protect this population, in April 2020, the Israeli government launched a national-level task force, “Senior Shield,” that aimed to support long-term care facilities in managing the Covid-19 crisis. The main efforts included supplying personal protective equipment, initiating weekly screening of health care workers with polymerase-chain-reaction (PCR) assays along with other outbreak-containment measures, and assigning responsibility for administering two doses of the BNT162b2 (Pfizer–BioNTech) vaccine. In June and July of 2021, a surge in Covid-19 cases occurred in Israel, including among vaccinated persons and with increased outbreaks in long-term care facilities. The surge was attributed to waning vaccine-induced immunity and the rapid spread of the B.1.617.2 (delta) variant.

Consequently, on July 30, 2021, the Ministry of Health approved the administration of a BNT162b2 booster vaccine (third dose) for persons 60 years of age or older who had received the second vaccine dose at least 5 months earlier; the approval was later extended to persons under 60 years of age. This approval prompted an immediate nationwide 3-week campaign of administering the BNT162b2 booster to residents in long-term care facilities between August 1 and August 22, 2021.

Researchers evaluated the changes in the incidence of Covid-19 among such residents during the 5 weeks before and 6 weeks after the initiation of this campaign and compared the results with those in the general population. The surveillance included data for 41,623 residents of long-term care facilities who were 60 years of age or older, 1,521,340 persons in the same age group in the general population, 4,515,314 persons between the ages of 20 and 59 years, and 3,299,121 persons under 20 years of age. The BNT162b2 booster campaign in the long-term care facilities was characterized by a rapid implementation and the figure shows the proportion of all residents of long-term care facilities according to their immune-status category and the time period. The uptake of the booster dose among persons who were 60 years of age or older in the general population was lower than that among the residents of long-term care facilities, and the uptake was lowest among persons in the younger age groups.

During the booster period, the dynamics of Covid-19 incidence differed among the groups. Among the residents of long-term care facilities, significantly lower rates of SARS-CoV-2 infection and hospitalisation for severe Covid-19 were observed starting at week 34 as compared with week 31 (the first week of the booster program). By week 36, the incidence rate ratio had reached 0.29 for overall infection and 0.20 for hospitalisation, which corresponded to a relative rate reduction of 71% and 80%, respectively. Among persons who were 60 years of age or older in the general population, the decline after booster vaccination was of lower magnitude and was observed for all SARS-CoV-2 infections during weeks 35 and 36 only, with no significant decrease in the risk of hospitalisation for severe disease. Among persons who were younger than 60 years of age, no significant decreases were observed in the incidence of either infection or hospitalisation during the study period. Generally, mortality was higher among residents of long-term care facilities than among other groups. Rates of death varied widely during the booster period among the residents of long-term care facilities, with a decrease from 0.3 per 1000 population in week 34 to 0.1 per 1000 population in week 36. The rate of death continuously increased in the general population in the same age group, from 0.05 per 1000 population in week 31 to 0.1 per 1000 population in week 36.

In a previous study involving participants who were 60 years of age or older and had received two doses of the BNT162b2 vaccine at least 5 months earlier, the rates of confirmed Covid-19 and severe illness were substantially lower among those who had received a booster dose. In the current study, after the initiation of an intensive BNT162b2 booster campaign with high vaccine uptake, they found a significant, rapid, and consistent reduction in the Covid-19 burden among persons in the same age group who were living in long-term care facilities. The reduction in the incidence of Covid-19 infection was delayed and of a lower magnitude among persons in the same age group in the general population during the booster period; among the younger age groups, no significant decreases were noted. Our results suggest the important real-life effects of the nationwide BNT162b2 vaccine booster program among residents in long-term care facilities:

https://www.nejm.org/doi/full/10.1056/NEJMc2117385?

Do patients infected with the SARS-CoV-2 Delta variant experience more severe disease outcomes compared with those infected with the Beta variant? In this cohort study of 1427 persons infected with the Delta variant and 5353 persons infected with the Beta variant in Qatar, among 451 propensity score–matched pairs identified, persons infected with the Delta variant were more likely to be hospitalized (27.3% vs 20.0%) or to experience more severe disease outcomes. Infection with the Delta variant was independently associated with higher odds of experiencing any adverse outcome, and vaccination was associated with significantly reduced odds of severe disease outcomes. In this cohort study, infection with the Delta variant was more severe than infection with the Beta variant in persons in Qatar, although vaccination was highly protective against severe outcomes for both variants:

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2787492

Researchers’ results suggest a modest reduction in vaccine effectiveness against COVID-19 in Utah associated with the expansion of the Delta lineage in the state. This reduction in the effectiveness of available vaccines associated with the arrival of novel VOCs, rather than waning immunity, is concerning. These should serve as a caution throughout the US that the Delta variant can bring renewed outbreaks, even in highly vaccinated populations. If there is a consistent trend of increasing immune escape as new variants arise, it could eventually undermine the effectiveness of current vaccines and necessitate mass revaccination:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787438

A study aimed to assess the impact of COVID-19 on routine immunisation using triangulated data from global, country-based, and individual-reported sources obtained during the pandemic period. This report synthesised data from 170 countries and territories. Data sources included administered vaccine-dose data from January to December, 2019, and January to December, 2020, WHO regional office reports, and a WHO-led pulse survey administered in April, 2020, and June, 2020. Results were expressed as frequencies and proportions of respondents or reporting countries. Data on vaccine doses administered were weighted by the population of surviving infants per country. A decline in the number of administered doses of diphtheria–pertussis–tetanus-containing vaccine (DTP3) and first dose of measles-containing vaccine (MCV1) in the first half of 2020 was noted. The lowest number of vaccine doses administered was observed in April, 2020, when 33% fewer DTP3 doses were administered globally, ranging from 9% in the WHO African region to 57% in the South-East Asia region. Recovery of vaccinations began by June, 2020, and continued into late 2020. WHO regional offices reported substantial disruption to routine vaccination sessions in April, 2020, related to interrupted vaccination demand and supply, including reduced availability of the health workforce. Pulse survey analysis revealed that 45 (69%) of 65 countries showed disruption in outreach services compared with 27 (44%) of 62 countries with disrupted fixed-post immunisation services. The marked magnitude and global scale of immunisation disruption evokes the dangers of vaccine-preventable disease outbreaks in the future. Trends indicating partial resumption of services highlight the urgent need for ongoing assessment of recovery, catch-up vaccination strategy implementation for vulnerable populations, and ensuring vaccine coverage equity and health system resilience:

https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00512-X/fulltext

In a retrospective, population-based cohort study in Brazil and Scotland, researchers linked national databases from the EAVE II study in Scotland; and the COVID-19 Vaccination Campaign, Acute Respiratory Infection Suspected Cases, and Severe Acute Respiratory Infection/Illness datasets in Brazil) for vaccination, laboratory testing, clinical, and mortality data. They defined cohorts of adults (aged ≥18 years) who received two doses of ChAdOx1 nCoV-19 and compared rates of severe COVID-19 outcomes (ie. COVID-19 hospital admission or death) across fortnightly periods, relative to 2–3 weeks after the second dose. 1,972,454 adults received two doses of ChAdOx1 nCoV-19 in Scotland and 42,558,839 in Brazil, with longer follow-up in Scotland because two-dose vaccination began earlier in Scotland than in Brazil. In Scotland, RRs for severe COVID-19 increased to 2·01 (95% CI 1·54–2·62) at 10–11 weeks, 3·01 (2·26–3·99) at 14–15 weeks, and 5·43 (4·00–7·38) at 18–19 weeks after the second dose. The pattern of results was similar in Brazil, with RRs of 2·29 (2·01–2·61) at 10–11 weeks, 3·10 (2·63–3·64) at 14–15 weeks, and 4·71 (3·83–5·78) at 18–19 weeks after the second dose. In Scotland, vaccine effectiveness decreased from 83·7% (95% CI 79·7–87·0) at 2–3 weeks, to 75·9% (72·9–78·6) at 14–15 weeks, and 63·7% (59·6–67·4) at 18–19 weeks after the second dose. In Brazil, vaccine effectiveness decreased from 86·4% (85·4–87·3) at 2–3 weeks, to 59·7% (54·6–64·2) at 14–15 weeks, and 42·2% (32·4–50·6) at 18–19 weeks. They found waning vaccine protection of ChAdOx1 nCoV-19 against COVID-19 hospital admissions and deaths in both Scotland and Brazil, this becoming evident within three months of the second vaccine dose. Consideration needs to be given to providing booster vaccine doses for people who have received ChAdOx1 nCoV-19:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02754-9/fulltext

Current vaccines are based on the original SARS-CoV-2 strain and are designed primarily to raise an antibody response against the spike protein (S), although elicited T-cell responses can also contribute to protection from severe disease. The SARS-CoV-2 RNA polymerase is intrinsically error prone, which results in mutation to the viral genome. In the past year, several variants containing multiple mutations in S have been reported: alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2). These variants contain mutations in the receptor binding motif, a small 25 amino acid patch at the tip of S that mediates interaction with the ACE2 receptor (one mutation in alpha, three in beta and gamma, and two in delta). These changes can lead to increased transmissibility by increasing affinity to ACE2 (by seven times for alpha, 19 times for both beta and gamma, and double for delta) or lead to immune escape. First alpha and then delta variants spread globally causing successive waves of infection, while large localised outbreaks were caused in southern Africa by the beta variant and in South America by the gamma variant. Omicron contains a large number of mutations in S compared with previous variants of concern, mostly concentrated around the receptor binding motif: 30 amino acid substitutions, deletion of six residues, and insertion of three residues. Mutations are also present at other sites (receptor binding domain and N-terminal domain) which might affect neutralising antibodies. There is concern that omicron will lead to increased propensity to infect individuals who have received vaccines, whose antigens are based on the original S sequence.

Here, researchers report the results of neutralisation assays using an isolate of omicron obtained from an infected case in the UK. Neutralisation assays were done on sera from individuals from the immunology cohort of the Com-COV2 study, who were seronegative at enrolment (defined by anti-nucleocapsid IgG). Participants were vaccinated with two doses of Oxford–AstraZeneca's ChAdOx1 nCoV-19 (ChAd; n=22), or two doses of Pfizer–BioNTech's BNT162b2 (BNT; n=21) with a priming interval of 8–11 (median 9) weeks. Samples were obtained 28 days (range 25–32) following the second immunisation. Live virus neutralisation titres against omicron are compared with titres against Victoria, an early pandemic SARS-CoV-2 strain, together with titres against beta and delta variants.

Neutralising titres on sera from participants who had received homologous ChAd dropped to below the detectable threshold in all but one participant. Median neutralising titres on sera from participants who had received homologous BNT reduced by 29·8 fold from 1609 (Victoria strain) to 54 (omicron variant), with one participant dropping below the detection threshold. In most cases, samples that did not neutralise with 50% focus reduction neutralisation titres at a dilution of less than 1/20 showed some residual neutralising activity:

In summary, there was a substantial decrease in neutralisation titre in recipients of both homologous ChAd and BNT primary courses, with evidence of some recipients not neutralising at all. This reduction in neutralisation titre will probably be more pronounced at later timepoints. These data, although derived from a relatively small sample size, are consistent with published data from datasets of similar size. Together, the findings suggest that omicron is more antigenically distant from the original SARS-CoV-2 vaccine strain than the previously most distant strains, beta and delta. Preliminary data from the UK Health Security Agency have shown reduced effectiveness against symptomatic infection after two doses of ChAd or BNT, suggesting a result of increased breakthrough infections in previously infected or double vaccinated individuals, which could drive a further wave of infection. The effect on disease severity is unknown, although there is currently no evidence of increased potential to cause severe disease, hospitalisation, or death. It could be that other aspects of the immune response such as non-neutralising antibodies and cellular immunity, which are not expected to be as severely affected by this variant, could confer a degree of protection against severe disease. However, it should be noted that higher transmission will inevitably lead to increased numbers of cases and a greater burden on health systems, even without proportional changes in severity. Possessing a high starting neutralisation titre against early pandemic strains gives a higher level of neutralisation of omicron, which could be obtained by deploying third booster doses of vaccine.

Should omicron, as expected, become the dominant strain worldwide, given its antigenic distance from ancestral strains, it could be necessary to produce vaccines tailored to omicron; however, these might be unlikely to give protection against previous strains. This development might stimulate consideration of a switch from the current monovalent vaccine strategy towards multivalent formulations currently used in seasonal influenza vaccines. In the meantime, reaching people who are unvaccinated with current vaccines is a priority, in order to reduce transmission levels and the potential for severe disease in people who are immunologically naïve:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02844-0/fulltext

T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. A group assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with the Beta variant (dominant from November 2020 to May 2021) or infected prior to its emergence (first wave, Wuhan strain), to provide an overall measure of immune evasion. Researchers show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first wave patients. Using peptides spanning the Beta-mutated regions, they identified CD4 T cell responses targeting the wild type peptides in 12/22 first wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. Among the spike epitopes tested, they identified three epitopes containing the D215, L18, or D80 residues that were specifically recognized by CD4 T cells, and their mutated versions were associated with a loss of response. This study shows that in spite of loss of recognition of immunogenic CD4 epitopes, CD4 and CD8 T cell responses to Beta are preserved overall. These observations may explain why several vaccines have retained the ability to protect against severe COVID-19 even with substantial loss of neutralizing antibody activity against Beta:

https://www.science.org/doi/10.1126/scitranslmed.abj6824

Researchers used golden hamsters as a model to study the immune responses to SARS-CoV-2 infection. They found that SARS-CoV-2 infection induced immune responses different from influenza infection but could effectively lead to memory B and T cell responses. The generated memory T cells were able to protect against SARS-CoV-2 reinfection of animals with the same strain and a variant of concern. Despite immunity and protection to reinfection, hamsters with SARS-CoV-2 immune memory could still transmit the virus to naïve cage mates. Thus, golden hamsters represent a robust model for studying the immune responses to SARS-CoV-2 infection:

https://www.science.org/doi/10.1126/sciimmunol.abm3131

Merck conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalisation or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. A total of 1433 participants underwent randomisation; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalisation for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomisation, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. Early treatment with molnupiravir reduced the risk of hospitalisation or death in at-risk, unvaccinated adults with Covid-19:

https://www.nejm.org/doi/full/10.1056/NEJMoa2116044?query=recirc_mostViewed_railB_article

Some of this tragedy could have been averted with the development of deliverable, orally bioavailable, direct-acting antiviral therapeutics. Molnupiravir, the orally bioavailable prodrug of N4-hydroxycytidine (NHC), begins to address this need. Synthesized at the Emory Institute for Drug Development (EIDD), molnupiravir is active against influenza as well as multiple other RNA viruses, including SARS-CoV-2. As the coronavirus pandemic emerged, EIDD developed molnupiravir for the treatment of pathogenic coronavirus infections rather than influenza. This decision was based on an extensive body of work performed in cell culture and in animal models of SARS, MERS, and ultimately, SARS-CoV-2. NHC is phosphorylated intracellularly to its triphosphate derivative, which is incorporated into viral RNA, leading to fatal errors in replication. An added benefit is a high genetic barrier to resistance.

Above are the results of a phase 2–3 placebo-controlled trial of molnupiravir that may begin to address this global problem. The drug was administered orally (800 mg [four tablets] twice daily for 5 days) and compared with a matching placebo. Patients with mild-to-moderate disease and at least one risk factor for progression to severe illness (including age >60 years, obesity, diabetes, or cardiovascular disease) were eligible for enrllment. The primary end point was a composite of hospitalisation or death at 29 days. At the planned interim analysis, 775 patients who were infected with SARS-CoV-2 and had symptoms of no more than 5 days’ duration were enrolled; 387 patients received molnupiravir and 388 received placebo. The prespecified interim analysis was performed at approximately 50% of the planned enrolment. In the molnupiravir group, the risk of hospitalisation or death was 7.3% (28 of 385 patients), as compared with 14.1% (53 of 377) in the placebo group (P=0.001); no deaths had occurred in the molnupiravir group at the time of this interim analysis. However, the final analysis of these peer-reviewed data shows a more modest effect. In the final data, 1433 infected volunteers were randomly assigned to molnupiravir (716 patients) or placebo (717 patients). A primary end-point event occurred in 48 of 709 molnupiravir recipients (6.8%) and 68 of 699 placebo recipients (9.7%), an absolute difference of approximately 3 percentage points. One death occurred in the treatment group, and nine among placebo recipients. Numerous potential reasons for the lessening of the drug effect include preexisting SARS-CoV-2 nucleocapsid antibodies and lower viral load at enrolment.

In the patients with available sequence data, molnupiravir was found to be active against the three predominant circulating variants (delta, gamma, and mu) and showed a modest antiviral effect. Adverse events were similar in the two groups.

This clinical trial potentially provides a tool in the management of Covid-19, pending evaluation by the FDA, the European Medicines Agency, and other licensing bodies. Several points warrant emphasis. First, molnupiravir therapy was initiated within 72 hours after symptom onset in nearly 50% of patients; however, one must strive for therapy to begin within 72 hours in all patients, as shown in studies of influenza. Since SARS-CoV-2 infection must be confirmed, a point-of-care companion diagnostic test would be of value. Molnupiravir is less beneficial when administered late in the disease course — namely, after patients have had symptoms for more than 3 to 5 days or after they are hospitalized, as shown in reports of two phase 2 trials of molnupiravir. Second, the safety database is small and will require careful monitoring for the emergence of side effects. Third, potential mutagenic toxicity has been a concern, since the drug is mutagenic in Chinese hamster ovary cells. However, there is a body of data that address concerns related to the potential mutagenicity and genotoxicity of molnupiravir. Given the totality of data, regulatory authorities in the United Kingdom have stated that the risk of mutagenicity or genotoxicity in the clinical use of molnupiravir is low, and it was licensed for use in the United Kingdom on November 4, 2021. The U.K. summary report on molnupiravir recommends licensure for SARS-CoV-2–infected persons 18 years of age or older who have one risk factor for progression to severe illness — a population similar to that described in the article above. The report notes a low risk of genotoxicity, a concern for some physicians. Molnupiravir was not recommended for women who are pregnant or breast-feeding or for those who might become pregnant during treatment. The FDA will review these data, most likely before the end of the year, in considering an Emergency Use Authorisation. Fourth, the sponsor has indicated in the lay press that drug patents will be made available to the WHO patent pool and to manufacturers of generic drugs so that molnupiravir can be produced for developing countries, ideally at low cost.

Vaccines must be the primary mode of protection against SARS-CoV-2; however, orally bioavailable medications will become an essential tool for physicians in the management of this horrible disease. Of note, although the data have not been peer-reviewed, Pfizer has announced the efficacy of its orally bioavailable protease inhibitor, Paxlovid, and Gilead has reported a benefit of ambulatory therapy with remdesivir. Data for both medications demand peer review. The availability of medications with different mechanisms of action offers the opportunity for creating combination therapies that are potentially synergistic and less likely to lead to resistance.

In another molnupiravir study, researchers evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and with symptom duration <7 days. Participants were randomized 1:1 to receive 200 mg molnupiravir or placebo, and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800 mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank p-value=0.013). 92.5% of participants receiving 800 mg molnupiravir achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800 mg molnupiravir group compared with 16.7% of placebo group at day 3 of treatment (p =0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg molnupiravir compared with 11.1% of placebo recipients (p =0.034 and 0.027, respectively). Molnupiravir was well tolerated, with a similar number of adverse events across all doses:

https://www.science.org/doi/10.1126/scitranslmed.abl7430

Finally today, humans have infected a wide range of animals with SARS-CoV-2 viruses, but the establishment of a new natural animal reservoir has not been observed. Here, we document that free-ranging white-tailed deer (Odocoileus virginianus) are highly susceptible to infection with SARS-CoV-2 virus, are exposed to a range of viral diversity from humans, and are capable of sustaining transmission in nature. SARS-CoV-2 virus was detected by rRT-PCR in more than one-third (129/360, 35.8%) of nasal swabs obtained from Odocoileus virginianus in northeast Ohio (USA) during January-March 2021. Deer in 6 locations were infected with 3 SARS-CoV-2 lineages (B.1.2, B.1.582, B.1.596). The B.1.2 viruses, dominant in humans in Ohio at the time, infected deer in four locations. Probable deer-to-deer transmission of B.1.2, B.1.582, and B.1.596 viruses was observed, allowing the virus to acquire amino acid substitutions in the spike protein (including the receptor-binding domain) and ORF1 that are infrequently seen in humans. No spillback to humans was observed, but these findings demonstrate that SARS-CoV-2 viruses have the capacity to transmit in US wildlife, potentially opening new pathways for evolution. There is an urgent need to establish comprehensive “One Health” programs to monitor deer, the environment, and other wildlife hosts globally:

https://www.nature.com/articles/s41586-021-04353-x

Graphs:

Emerging hot spots in the US. The x-axis is growth rate of new cases compared to last week, the y-axis is the new case per hundred, and z is the latitude. Each state is colour coded by vaccination rate:


Justin Stebbing
Managing Director

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