As Spain, Italy and Australia relax isolation and testing rules, WHO emergencies director Michael Ryan told a news conference: “If people shorten the quarantine period, there will be a small number of cases that will develop disease and potentially go on to transmit, because they have been let out of quarantine earlier. But that will be a relatively small number, and a lot of people who won’t transmit will also be released from that quarantine. So it is a trade-off between the science and being absolutely perfect in what you try to do, but then having the minimal disruption that you can possibly have to your economy and society - and governments are struggling to find that balance.” I note cases in India are climbing rapidly, though no records being broken unlike in Europe. Also have to say I found the videos of Covid rule breakers being paraded through streets of China in hazmat suits disconcerting:
RNA data and diagnosed cases have converged here. Wastewater data from the Boston area shows that copies of Covid RNA/mL have surged and current diagnosed cases have now risen to meet the RNA data. One can consider two possibilities: (1) increase in testing due to holiday travel and (2) more symptomatic cases:
US hospital admissions appear to not be accelerating with the increase in confirmed Covid cases. In the UK, confirmed Covid cases have skyrocketed, but hospitalizations have not increased in the same manner as during previous waves. In South Africa, both cases and hospitalization have appeared to have turned downwards:
We are now more than 25 days into the omicron wave in South Africa. Looking at the previous two waves, with omicron’s first 25 days defined as November 14 to December 8, hospital admissions data is promising. Broken down on an age basis, the percentage of Covid admissions that were severe are much lower at the beginning of the current wave (grey) than in previous waves (blue, orange). Even looking at the number of admissions by ward, the overall number of admissions is lower, and the admissions that were to either High Care or ICU are significantly lower than in the previous two waves:
Below shows the countries with the largest increase in diagnosed cases from Nov 1 to now. Figure 11 on the right below shows vaccination rates and hospital capacity, estimated using World Bank annual data. Countries with lower vaccination rates and hospital capacity (bottom left of chart) would be more vulnerable in the event of a virus outbreak:
If you use the max hospitalizations at any time during the Covid-19 pandemic as the current 100% capacity. Data shown in light blue is frequently revised. In the majority of countries we are far from pandemic highs of hospitalization:
Authors of the below study, released by Bentonville-based Heartland Forward, note they couldn't capture the many intangible benefits, such as the sense of hope and optimism, increased quality of life and improved mental health as a return to normal became reality:
Now mandatory vaccinations. On Dec 9, 2021 the Austrian Government laid a bill before parliament that would impose a mandatory COVID-19 vaccination requirement for all its residents. This move followed the Greek Prime Minister's announcement to impose fines on residents aged 60 years and older who do not take up COVID-19 vaccination. Many other nations are contemplating similar mandates or have adopted mandates in certain workplace settings, such as Australia, Brazil, Canada, France, Indonesia, Italy, and the UK. Some people resist vaccine mandates on pragmatic grounds, for example, that such mandates could decrease health-care staffing levels or morale. However, mandatory vaccination is also often opposed in principle. The UK Secretary of State for Health and Social Care, Sajid Javid, for instance, told the BBC on Dec 10, 2021 that he thought mandatory vaccination is “unethical”.
Many others presume mandatory vaccination violates human rights. An editorial group in the Lancet believe that this view is mistaken, at least as a matter of international and comparative constitutional law. Their opinion is based on extensive discussion and analysis held as part of the Lex-Atlas: Covid-19 (LAC19) project, a worldwide network of jurists that is producing and curating the open-access Oxford Compendium of National Legal Responses to Covid-19. 50 jurists in the network adopted principles concerning the legality and constitutionality of mandatory vaccination in October, 2021 (the LAC19 Principles).
They concluded that mandatory vaccination and human rights law are compatible in principle and that there is a compelling rights-based case for a state duty to consider adopting mandatory vaccination, defined as any law that makes vaccination compulsory, or any public or private vaccination requirement for accessing a venue or service that cannot be avoided without undue burden. This definition recognises mandates adopted by public and private bodies and, crucially, that requirements avoidable through affordable testing are not mandatory.
Even on the most libertarian understanding of liberty, philosophers and jurists agree that restrictions on liberty can be justified if they prevent harm to others. The European Convention on Human Rights recognises this by considering the right to physical integrity under article 8 to be a “qualified right” that can be limited “for the protection of health”. If a mandatory vaccination scheme aims in part or whole to reduce harm to others, it is not paternalistic.
But liberty is not the only value relevant to human rights law. Economic and social rights to health, work, and education have been recognised in international law since 1948, most comprehensively in the UN International Covenant on Economic, Social and Cultural Rights (ICESCR), an international treaty ratified by 171 states, including all those in Europe and the UK. In its 2013 Global Vaccine Action Plan, WHO reinforced the view that “immunization is, and should be recognized as a core component of the human right to health and an individual, community and governmental responsibility”. A similar view was recognised in article 12(c) of the ICESCR, which lists “the prevention, treatment and control of epidemic… diseases” as among the obligations entailed by the right to health.
Mandatory vaccination is not a knee-jerk response to COVID-19. In more than 100 countries there already exist some version of mandatory vaccination of school children for a range of diseases, including measles, mumps, rubella, tetanus, and polio. In April, 2021 Chile, Germany, Israel, Mexico, Norway, Serbia, Spain, and a number of states in the USA had pre-pandemic laws that gave legal authority to impose vaccination mandates against COVID-19 in particular. As far as they know, no major constitutional or international court has found that a mandatory vaccination policy violates any general right to liberty. Many such policies have been upheld when challenged. In April, 2021 in relation to a pre-COVID-19 law, the Grand Chamber of the European Court of Human Rights found that a Czech law requiring compulsory vaccination of children against nine diseases did not violate the article 8 right to physical integrity because the scheme was a proportionate means of protecting public health.
In several other jurisdictions, courts have reached the same or similar conclusions, including the US Supreme Court's ruling in Jacobson v Massachusetts (1904), recent pre-COVID-19 judgments that uphold mandatory vaccination schemes in France, Italy, and Chile, and COVID-19-specific decisions for programmes in New York and Brazil. In most of these decisions, the courts found the schemes gave effect to the right to health. Nevertheless, the in-principle compatibility of mandatory vaccination and human rights does not mean that governments, employers, or schools should be cavalier about their adoption. They certainly interfere with fundamental rights, so careful design is required to ensure that vaccine mandates do not violate rights. The LAC19 Principles thus aim to provide guidance on how to enact rights-compliant schemes.
The LAC19 Principles recommend that mandatory vaccination schemes must be prescribed by law that is clear and preferably adopted after consultation. Ideally, mandatory vaccination should be regulated by statute, rather than executive rules (ie, regulations). The making of mandatory vaccination laws should undergo a period of consultation of at least 4–6 weeks and involve subnational governments, opposition parties, trade unions, experts, the public, and others. These consultations, and the government's response, should be published before the passage of any bill, to allow for debates and amendments. Consistently with widely accepted constitutional principles that relate to the non-delegation of core legislative functions, mandatory vaccination laws should not leave major policy questions for governments, private businesses, or employers. They should be addressed in the bill going through the legislature, allowing for debate and amendments.
Mandatory vaccination schemes must also meet the legal principle of proportionality. As detailed in the LAC19 Principles, the scheme must have a legitimate aim, eg. the reduction of virus transmission or protection of health services. The means chosen must be rationally connected to that aim. In practice, proportionality will be satisfied if the mandatory vaccination scheme is based clearly on sound public health advice. The scheme must also be necessary in the sense that there is no other less-impairing means of achieving that aim. Here there will be much debate about vaccine efficacy and probable social responses to mandatory vaccination. Public law principles counsel judicial restraint on a question as complex as the epidemiological necessity of a nationwide vaccine mandate. Finally, fines and punishments for not complying with the mandate should be effective but not be too onerous. The more severe the penalty, the more vulnerable is the policy to a legal finding of disproportionality.
The LAC19 Principles also call for constructive engagement with reasonable vaccine hesitancy. The political philosopher John Rawls famously distinguished what is rational from what is reasonable. Vaccine hesitancy may be reasonable (understandable and respect-worthy) for some groups who are suspicious of vaccine mandates, eg. communities who have been subject to state-complicit persecution, discrimination, marginalisation, or neglect. In such cases, the state and other actors should adopt constructive engagement interventions with these groups, such as community-led education or delayed commencement periods. Blunt termination notices on their own are insufficient. However, constructive engagement falls short of offering full exemptions. Medical exemptions should be considered, but exemptions for religious beliefs or freedom of conscience are not generally required by human rights law. Although mandatory vaccination requirements must be designed with great care, there is no reason to think they are inherently incompatible with human rights law:
A group describe the long, windy, treacherous journey to vaccinate indigenous tribes in the Amazon:
A group report a super-spreading event of Omicron infections amongst triple-vaccinated healthcare workers, infecting 21 of 33 attending a private gathering in the Faroe Islands.
In late November 2021, an outbreak of Omicron SARS-CoV-2 following a Christmas party with 117 attendees was detected in Oslo, Norway. They observed an attack rate of 74% and most cases developed symptoms. As at 13 December, none have been hospitalised. Most participants were 30–50 years old. Ninety-six percent of them were fully vaccinated. These findings corroborate reports that the Omicron variant may be more transmissible, and that vaccination may be less effective in preventing infection compared with Delta:
Biological E announced that the company’s COVID-19 vaccine Corbevax, adjuvanted with Dynavax’s CpG 1018 plus alum, received approval from the Drug Controller General of India. This announcement came quickly on the heels of news yesterday that the Subject Expert Committee recommended emergency-use authorization for the vaccine. Corbevax now represents the second CpG 1018 adjuvanted COVID-19 vaccine to receive regulatory approval following the approval of Medigen’s vaccine in Taiwan, and the fourth CpG 1018 COVID-19 vaccine to demonstrate efficacy in late-stage clinical trials. While limited data was disclosed from the clinical trials of Corbevax, Bio E’s press release indicated that the vaccine demonstrated superior efficacy compared to Covishield (AstraZeneca’s vaccine) as determined by geometric mean titers (GMT) of neutralizing antibodies against both the original strain and Delta variant. Against the Delta variant specifically, Corbevax was noted to demonstrate >80% efficacy in preventing symptomatic infections, potentially coming in slightly below what has been observed with mRNA vaccines and similar to the 78.7% efficacy observed with Clover Biopharmaceuticals’s CpG 1018 adjuvanted vaccine. Also of note, neutralizing antibody GMTs were noted to decrease by less than 30% at 6 months following the second dose of Corbevax, less of a decrease in titers than has been observed with other COVID-19 vaccines, though this could be due to the patient demographics and more data is needed to see if this translates to longer-term protection.
Notably, while detailed safety data was not disclosed, Corbevax was found to be associated with 50% fewer adverse events compared to Covishield, with no serious adverse events reported. These results are consistent with what has been reported from other CpG 1018 containing COVID-19 vaccines, with CpG 1018 enabling both an effective immune response coupled with a differentiated safety profile highlighting its utility as a vaccine adjuvant. This utility has now been demonstrated across numerous vaccine technology platforms, including protein sub-unit (Medigen/Bio E), inactivated whole virus (Valneva), and S-Trimer protein (Clover Bio) vaccines, which we believe provides Dynavax with validation of the company’s adjuvant that could draw additional interest from vaccine development programs beyond COVID-19.
But, this aside, as we all know, the pandemic has disproportionately affected people living in care homes, who accounted for an estimated 30% of all deaths from covid-19 across 25 countries despite making up only 1% of the world’s population, a report has estimated.
The analysis was carried out by Collateral Global, a research group that says it is dedicated to reporting on the effects of governments’ mandatory covid-19 mitigation measures. The report said the pandemic had exacerbated long running problems in the care sector, such as chronic underfunding, poor structural organisation, staff undertraining, under-skilling, and under-equipping, and a “lack of humanity in dealing with the most vulnerable members of society.” “Neglect, thirst, and hunger were, and possibly still are, the biggest killers,” the group said. They also said that care home residents faced barriers in access to emergency treatments during the pandemic.
To carry out the analysis the group used national datasets on mortality from 25 countries, 17 cohort studies comparing deaths with a previous period, and 16 cohort studies reporting interventions or factors associated with excess mortality. The countries they looked at included the UK, US, Australia, Belgium, France, Canada, Israel, and France, but they emphasised that the quality of the evidence was limited and country comparisons should be treated with caution.
The report also looked at excess deaths, defined as the number of reported deaths from all causes during the crisis above what would be expected under non-crisis conditions. It said that all 17 cohort studies examined pointed to excess mortality worsening during the pandemic. However, the authors said that, despite the studies involving vast numbers of care homes around the world, the quality of the evidence was not good.
In England and Wales a study analysed the national death registry of all deaths of adults between March and June 2020 and compared these with historical data from January 2014 up to March 2020. A total of 57 860 excess deaths were reported, 44% of which (25,611) were in care homes or hospices. Of the 25 611 excess deaths in care homes and hospices, 61% (15,623) were due to covid-19, while 6267 were from dementia and 2358 from ill-defined conditions. There were also 1495 fewer deaths from cancer than expected, and 1211 excess deaths from cardiac disease. The study authors suggested that undiagnosed covid-19, poor testing, and inadequate staffing and infection control were the likely factors contributing to the excess deaths in care homes.
The report found that care homes with fewer beds were less likely to report covid deaths among residents. In the US, covid-19 cases and deaths were found to be at significantly lower rates in “Green House” homes, which usually have fewer than 12 beds, than in traditional homes that had either less than or more than 50 beds. As well as being less crowded, Green House residents also receive significantly more hours a day of care from certified nursing assistants than residents in traditional nursing homes.
The effects of chronic understaffing, whether this was due to pre-existing staffing shortages or workers becoming sick or leaving because of the pandemic, were also suggested as a contributing factor towards care home mortality. In some areas, such as in France and Spain, there were reports of long-term care residents being confined to their rooms for days without assistance with eating and drinking and nursing home residents being found in a “state of complete abandonment” by armed forces brought in to help. Looking at where care was good, the report pointed to US research that found that nursing homes with a five-star inspection rating had 24% lower numbers of deaths from covid than those with a one-star rating. Meanwhile, a French study found that mortality among covid patients decreased substantially if they had daily clinical examination or vital signs measurement. To reduce mortality among care home residents and improve the care they get, the report authors recommended increasing staffing levels, reducing the number of beds in facilities, employing staff confinement strategies with residents, and implementing clinical changes such as daily examinations.
Nadra Ahmed, chair of the National Care Association, said, “In preparation for the impact [of covid-19] governments across the world focused on making sure that their hospitals were ready for the inevitable support they would need and set about creating capacity by discharging people out of the acute settings into support services. What followed was a seeding of the virus into support settings, like care homes, at a time when there was little or no testing available. “Clearly, care settings had not been adequately prepared, by any of the governments’ strategies to manage the crisis that followed, and we lost residents who already had complex healthcare conditions, which was why they were in a care setting in the first place. The reality is that in the absence of a plan to support and protect older people in care settings we saw the consequences unfold in a way that potentially saw people losing their lives prematurely.”
Martin Green, chief executive officer of Care England, said, “Adult social care and the NHS are two sides of the same coin and need to be treated as such. The government shouldn’t have placed such a myopic focus on the NHS without due consideration for social care too.” He said that he was “phenomenally” proud of the care workforce and wanted to ensure that they were recognised as professionals with proper career pathways and commensurate funding:
Death reporting in India. Between March 1, 2020, and June 30, 2021, 87,870 deaths were registered in areas of Chennai district represented by the 2011 census, exceeding expected deaths by 25 990 (95% uncertainty interval 25 640–26 360) or 5·18 (5·11–5·25) excess deaths per 1000 people. Stratified by age, excess deaths numbered 21·02 (20·54–21·49) excess deaths per 1000 people for individuals aged 60–69 years, 39·74 (38·73–40·69) for those aged 70–79 years, and 96·90 (93·35–100·16) for those aged 80 years or older. Neighbourhoods with lower socioeconomic status had 0·7% to 2·8% increases in pandemic-associated mortality per 1 SD increase in each measure of community disadvantage, due largely to a disproportionate increase in mortality within these neighbourhoods during the second wave. Conversely, differences in excess mortality across communities were not clearly associated with socioeconomic status measures during the first wave. For each increase by 1 SD in measures of community disadvantage, neighbourhoods had 3·6% to 8·6% lower pandemic-associated mortality during the first 4 weeks of India's country-wide lockdown, before widespread SARS-CoV-2 circulation was underway in Chennai. The greatest reductions in mortality during this early lockdown period were observed among men aged 20–29 years, with 58% (54–62) fewer deaths than expected from pre-pandemic trends. Mortality in Chennai increased substantially but heterogeneously during the COVID-19 pandemic, with the greatest burden concentrated in disadvantaged communities. Reported COVID-19 deaths greatly underestimated pandemic-associated mortality:
Under-reporting of COVID-19 associated death is common in both high-income countries and low-income and middle-income countries [LMICs]. Additionally, the use of case-fatality ratio alone has led to underestimation of mortality due to SARS-CoV-2 infection. Hence, global bodies such as the CDC have adopted a calculation of excess all-cause mortality during a particular time frame to assess the gravity of the situation. In an observational study, the authors above assessed the excess mortality during the COVID-19 pandemic by calculating the difference between observed and expected mortality during the period between March 24, 2020, and June 30, 2021, in Chennai, India. To estimate expected mortality, they used regression models, with stratification by age and sex. Additionally, the authors measured changes in life expectancy and assessed how changes in all-cause mortality varied across communities with different socioeconomic contexts. During the study period, Lewnard and colleagues estimated 5·18 excess deaths per 1000 residents (a 41% increase compared with pre-pandemic period mortality), with a 4·75-times higher mortality during the peak of the second wave.
The COVID-19 pandemic has predominantly been a logistical crisis rather than a pure medical crisis wherein morbidity and mortality result mainly from lack of timely diagnosis and treatment, rather than failure of appropriate treatment. Health-care systems across the globe were inadequately prepared to handle the crisis, especially in LMICs such as India. They found a gross disparity between the government statistics on COVID-19 mortality versus the excess all-cause mortality they calculated on the basis of Chennai Civil Registration System (CRS) data. However, we argue that this excess all-cause mortality in Chennai not only represents the mortality attributable to COVID-19 per se, but also includes the COVID-19 deaths resulting from the logistical crisis resulting in suboptimal or absent management. A good proportion of this excess mortality could also include the excess deaths due to non-COVID-19 causes, as expected during this logistical crisis.
Documentation during the COVID-19 pandemic, when dealing with vast numbers of patients, is a daunting task. Although the Indian Government might have framed appropriate rules and regulations for testing, certifying, and so on, the implementation of such rules was extremely challenging during the pandemic. One needs to look closely at the local practice of how medical practitioners were filling death forms and certifying COVID-19 as the cause of death in the given government registry during this period. Deaths might have occurred after patients reached or registered at a health-care facility without being able to get tested or treated for COVID-19, and the patients dying even before reaching the health-care facility might have led to missed diagnoses of COVID-19 and erroneous reporting of the deaths as non-COVID-19-related. Whether the PCR testing was done in all such deaths (despite existing rules for a mandatory post-death RT-PCR test) before certification needs to be ascertained.
We must also remember the shortcomings of the RT-PCR test on which we depend for diagnosing this rapidly spreading virus. Up to a third of COVID-19 infections could be missed by single conventional RT-PCR test, and even with a second test, the sensitivity is only up to 79%.Notably, post-COVID-19 sequelae, such as life-threatening fungal infections and ischaemic events (stroke, myocardial infarction, and so on) due to the COVID-19-related prothrombotic state, might have also added to excess delayed mortalities. These deaths are unlikely to have been documented as due to COVID-19 in CRS data. Life-threatening thrombotic complications could be the initial presentation in a small percentage of COVID-19 cases, which could be missed by the attending health-care staff.
The occurrence of so-called happy hypoxemia, well described in COVID-19, might have further delayed the seeking of medical attention in some cases, until the patient was overtly sick, further increasing the death count even with appropriate treatment. A small proportion of the population might have initially visited local practitioners from alternative systems of medicine, which again could have contributed to a missed or delayed diagnosis and treatment, ultimately adding to the increased mortality.
Moreover, social issues such as reluctance to transfer older people (especially those who are staying alone with relatively poor quality of life) with respiratory symptoms to a health-care facility due to the fear or stigma associated with contracting COVID-19 might have additionally increased the mortality tally. Furthermore, lockdowns might have discouraged many people from seeking medical attention to some extent until they became overtly sick. Finally, there is an unsubstantiated perception that human and political factors might have influenced the documentation to some extent in certain countries.
In conclusion, the increased deaths in the second wave might have occurred not only due to the higher R0 and virulence of the delta strain (B.1.617.2) and laxity in COVID-19-appropriate behaviour (the public feeling that the game is over), but also due to the inadequate anticipation of the health systems and the logistical obstacles this creates both for health-care facilities and individuals in need of careL
Accumulating data suggest that treatment with anti-CD20 therapy, such as rituximab and ocrelizumab, puts patients at considerably increased risk of developing severe outcomes from COVID-19 (risk ratios ranging from 1·7 to 5·5 have been reported).
This reported risk emphasises how important it is that these patients develop protective immunity via COVID-19 vaccinations, but, unfortunately, studies have shown that humoral immune responses after COVID-19 vaccination are poor in patients with rheumatic diseases or multiple sclerosis who are taking anti-CD20 agents, even after two doses. T-cell immunity after COVID-19 vaccination might be relatively unaffected by rituximab, but results from studies have varied, and whether cellular immunity in the absence of humoral immunity provides sufficient protection against severe COVID-19 remains uncertain. Results of a 2021 case series of fully vaccinated patients with rheumatic diseases who became infected with breakthrough SARS-CoV-2 suggest that treatment with rituximab still increases the risk of a worse COVID-19 outcome.
Therefore, it is highly relevant to investigate the effects of a third COVID-19 vaccine dose in patients receiving rituximab and critically discuss the place of rituximab in treatment strategies for patients with rheumatic diseases. Researcherw evaluated the development of humoral and cellular immunity against SARS-CoV-2 after two and three COVID-19 vaccine doses in 87 patients with rheumatoid arthritis and 1114 healthy controls. All patients were treated with rituximab, and concomitant treatment with conventional synthetic disease-modifying antirheumatic drugs was paused 1 week before until 2 weeks after each vaccination. Classification of antibody respose (no response, weak response, and response) was based on immunoglobulin G antibody levels found in healthy controls. Only patients with a weak or absent antibody response after two vaccine doses received a third dose (n=49); healthy controls did not receive a third dose. Cellular analyses to evaluate CD4+ and CD8+ T-cell responses were done in a subset of randomly chosen participants (19 patients and 20 healthy controls after the second vaccine dose, and 12 patients after the third vaccine dose). In line with previous studies, they observed that the majority of rituximab-treated patients (54 [62·1%] of 87) had no serological response after two vaccine doses, compared with four (0·4%) of 1114 controls. A third dose only marginally improved seroconversion rates; 29 (59·2%) of 49 patients had no response and 12 (24·5%) had a weak antibody response. By contrast, T-cell responses after two vaccine doses were similar for patients and controls, and a third vaccine dose slightly increased SARS-CoV-2-specific CD4+ and CD8+ T-cell counts.
They showed that the effects of a third dose of COVID-19 vaccine on humoral and cellular immunity in patients with rheumatoid arthritis receiving rituximab are marginal and therefore unlikely to considerably improve humoral protection against severe COVID-19. Hence, now that the negative impact of rituximab on COVID-19 severity, even after vaccination, is becoming increasingly clear, the data further emphasise that physicians should be cautious when prescribing rituximab during the ongoing COVID-19 pandemic. Physicians always need to carefully weigh the benefits against the risks before prescribing immunosuppressive treatment, and normally this balance is in favour of benefit due to low absolute risk of becoming infected with a dangerous pathogen. During the COVID-19 pandemic, however, people are constantly at a substantial risk of becoming infected with SARS-CoV-2, which means that the risks of rituximab treatment become considerably more important. Because of this altered risk–benefit evaluation, it could be argued that physicians should discuss the necessity of rituximab with their patients, and, when possible, prescribe other treatments. Shared decision making will be of utmost importance in this process. Choosing alternative therapies while maintaining adequate rheumatic disease control is more challenging for diseases with less effective alternative treatment options to rituximab (eg. anti-neutrophil cytoplasmic antibody-associated vasculitis) than for diseases for which several alternatives with comparable effectiveness are available (eg, rheumatoid arthritis). Decisions to continue or discontinue rituximab treatment should therefore always be made individually and in consultation with the patients themselves, who should be made aware of the additional risks that rituximab treatment poses during the current COVID-19 pandemic.
In addition to implications for treatment strategies regarding rituximab itself, the data also have important implications for therapeutic strategies when patients receiving rituximab become infected with SARS-CoV-2. Data from the RECOVERY trial show that therapeutic monoclonal SARS-CoV-2 antibody infusions significantly reduced mortality in patients with severe COVID-19 who had no detectable SARS-CoV-2 antibodies before infection. As the majority of patients treated with rituximab do not develop detectable SARS-CoV-2 antibodies after vaccination, even after receiving a third vaccine dose, monoclonal antibody infusions could be an important therapeutic component for these patients. Moreover, because the risks of COVID-19 in patients receiving rituximab are substantial, they believe that therapeutic monoclonal antibody infusions should be considered for all these patients shortly after diagnosis of COVID-19 and before the development of severe disease manifestations. However, the neutralising efficacy of monoclonal antibody infusions, and thus subsequently the clinical efficacy, will decrease with the rise of new SARS-CoV-2 variants such as the omicron variant (B.1.1.529). In conclusion, the current literature suggests that treatment with rituximab during the ongoing COVID-19 pandemic puts patients at an increased risk of COVID-19-related hospitalisation and death, even after vaccination. Because the results from Jyssum and colleagues indicate that a third COVID-19 vaccination does not substantially improve humoral protection, physicians should discuss alternative therapies with patients who receive or would start treatment with rituximab, at least for the remainder of the COVID-19 pandemic. In addition, patients receiving rituximab should be actively advised to contact a physician as soon as they test positive for COVID-19, so that early treatment with monoclonal SARS-CoV-2 antibodies and antiviral therapy can be considered:
Now treatments. The research community has responded to the COVID-19 pandemic with innovative platform trials to address the need for rapid evaluation of novel agents using a common protocol, among them being RECOVERY, ACTIV, and Solidarity. Despite several successes with anti-SARS-CoV-2 monoclonal antibodies (mAbs) for treatment of mild or moderate COVID-19 in ambulatory patients, an effective SARS-CoV-2-specific treatment for patients with COVID-19 who are being treated in hospital (ie. hospitalised) has remained elusive.
The ACTIV-3 Therapeutics for Inpatients with COVID-19 (TICO) platform was developed to assess multiple candidate mAbs in individuals hospitalised with moderate or severe COVID-19 within 12 days of symptom onset. Now, the ACTIV-3 TICO Study Group report the results of two neutralising mAb treatments (sotrovimab and BRII-196 plus BRII-198) that were provided in addition to standard of care, typically including remdesivir and corticosteroids, in a double-blind, randomised fashion, predominantly before the availability of SARS-CoV-2 vaccines, and were compared with a pooled placebo group. Enrolment into the trial was stopped early after a prespecified interim futility analysis in 536 participants in the modified intention-to-treat population found no improvement in odds of favourable pulmonary outcome scores on day 5 after infusion with either sotrovimab or BRII-196 plus BRII-198 compared with placebo. By day 90, no difference was seen in the primary endpoint of sustained clinical recovery with either sotrovimab or BRII-196 plus BRII-198 compared with placebo, and composite safety outcomes were similar across the three groups.
Based on intriguing results from the RECOVERY study on efficacy of casirivimab–imdevimab (REGN-COV2) in patients hospitalised with COVID-19, which showed benefit only in people who were retroactively determined to be seronegative for anti-spike IgG at randomisation, similar serostatus-dependent effects could have been seen with sotrovimab or BRII-196 plus BRII-198, despite no overall benefit. In the study by the ACTIV-3/TICO Study Group, 513 of 536 patients in the mITT population had baseline anti-spike antibody levels measured, enabling a subgroup analysis stratified by serostatus. At the time of randomisation, 212 (41%) participants were positive for anti-spike neutralising antibodies. Non-significant heterogenous effects in time to sustained recovery by baseline anti-spike neutralising antibody status were identified in the BRII-196 plus BRII-198 group, but not in the sotrovimab group; the difference in effect was small, and all 95% CIs crossed 1 and overlapped. Notably, by contrast with the results of the RECOVERY trial, which found no treatment effect in seropositive individuals, there was a trend favouring placebo for the composite safety outcome up to day 90 among seropositive participants. Although the heterogeneity of effect for this outcome was significant, again, 95% CIs in both subgroups crossed 1 and were overlapping. Moreover, neither mAb showed benefit in analyses restricted to people with earlier disease (ie, those admitted within 5 days of symptom onset, those not on oxygen, or those on <4 L/min of supplementary oxygen).
The data from this well executed platform trial contribute to accumulating evidence that anti-SARS-CoV2 mAbs do not have a role for the treatment of moderate or severe COVID-19 in general inpatients, compounding null results first seen with convalescent plasma and then with bamlanivimab and casirivimab–imdevimab. Despite a tantalising signal of potential benefit of some agents in seronegative individuals hospitalised with COVID-19, the time-sensitive implementation of a therapy that requires baseline antibody testing, when turnaround time for in-hospital serological testing can be upwards of 48 h, is of questionable practicality, especially given the resource implications of mAb administration. Therefore, we would ask the next obvious question: is there a mechanistic rationale for use of neutralising antibodies in people who have already developed advanced COVID-19 pneumonia or acute respiratory distress syndrome (ARDS)? Whether administration of exogenous neutralising antibodies is unhelpful because most people have made endogenous antibodies by the time they develop severe disease or because neutralising antibodies have little role in mitigating the pathology driven by the hyper-inflammatory phase of COVID-19, or even exacerbate it, is as yet unknown.
We are increasingly finding indications that targeting SARS-CoV-2, whether through mAb neutralisation or with direct-acting antivirals (eg, remdesivir), might be of little importance once clinically significant lung damage has occurred. At this stage of disease, pathophysiology appears to be driven by a dysregulated host innate immune response, and immunomodulatory therapies (eg. baricitinib, corticosteroids and anti-cytokine antibodies) targeting these processes might provide the greatest clinical benefit:
There remains reasonable equipoise as to whether people who might never make endogenous antibodies (eg. severely immunocompromised individuals, who, in my experience, often remain seronegative into advanced disease, even after developing ARDS) could still benefit from exogenous mAbs once admitted to hospital with severe disease. People who are unlikely to develop endogenous antibodies in response to either vaccination or infection constitute a population who can be presumed seronegative at the time of therapeutic decision making, without requiring assessment of serological status. This immunocompromised population should be the exclusive focus of ongoing investigation of anti-SARS-CoV-2 mAbs in patients hospitalised with COVID-19. The ACTIV-3 TICO trial should be the final trial of anti-SARS-CoV2 mAbs in non-immunocompromised patients hospitalised with COVID-19:
In another treatment trial, researchers asked does colchicine prevent intubation and mortality in hospitalized patients with COVID-19 pneumonia? In this randomized clinical trial of 1279 patients hospitalized with COVID-19, patients allocated to receive colchicine plus usual care or to usual care alone demonstrated no significant difference in the coprimary outcome of mechanical ventilation or 28-day mortality. This randomized clinical trial found that colchicine did not significantly reduce the need for mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia:
Finally today, Kiniksa reported that the phase 3 mavrilimumab (an anti-GM-CSF-Rα monoclonal antibody (human isoform IgG4)) trial in COVID-19-related acute respiratory syndrome (ARDS) did not achieve the primary endpoint of proportion of patients alive and free of mechanical ventilation at Day 29.
Hospitalization in Gauteng:
Time series of primary series/booster vaccinations (top), new COVID cases (middle) and current hospitalisations due to COVID (bottom) in the US:
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:
Back to Work Chart and Upcoming Vaccine Catalysts:
Percentage of hospital bed utilisation by US State:
Daily vaccinations in key regions:
Vaccinations vs Deaths in various countries:
Vaccine orders by country. The number on top of each bar shows the % of the population that the orders in place can cover. Note that countries whose orders cover <25% of their population were excluded:
Google search interest of three terms regarding COVID vaccines over the past 3 months:
Daily vaccinations in the US and Google trends of keywords around vaccination:
Variant for children development timeline: