Theories that the virus was created as a biological weapon are based on “scientifically invalid claims” and disseminated by proponents “suspected of spreading disinformation”, according to a study by US intelligence agencies. Tonga – formerly one of the last countries in the world to have remained Covid-free – has recorded its first coronavirus case. And, Russia is at all time case highs. The UK will send 20m Covid vaccine doses to developing countries by the end of the year. China is clearly a country to watch right now (note the scale is a bit strange as the cases were massive in early 2020).
In news I found surprising, the FDA wants to think about Moderna’s vaccine in 12-17 year olds more, after myocarditis reports. This is the first time they’ve gone against the advice of one of their panels.
In the US, the CDC added mood disorders to the list of conditions that put people at high risk of developing severe Covid-19. Doctors said the move was a welcome one, as the scientific seal of approval makes millions of people eligible for booster shots based on their mental health diagnosis and gives vulnerable people more of a reason to protect themselves. “This is a population that is really, really at risk due to the way that covid-19 interacts with the diagnoses,” said Lisa Dailey, executive director of the Treatment Advocacy Center. “Until the CDC put this group of disorders on their list, they would not have known that”. The list of those qualifying for booster shots includes mostly physical conditions that make someone likely to be hospitalized, like having cancer, diabetes, or suffering from obesity. The addition of “mood disorders, including depression, and schizophrenia spectrum disorders” could put millions of Americans on notice and public health experts say it is critical for these populations to take precautions. The list of conditions is not intended to be comprehensive and has been updated frequently throughout the pandemic.
Thanks to Covid’s near-stranglehold on health care in 2020, routine childhood immunizations have fallen around the world to levels last seen in 2014 for polio and measles vaccinations and in 2009 for the combined shot against diphtheria, tetanus, and pertussis. A new global report from the CDC says 17.1 million children did not receive their first DTP doses in 2020, an increase of 3.5 million children from 2019; approximately 3 million more children did not complete the infant vaccination series in 2020 than the year before. Coverage for Haemophilus Influenzae type b, hepatitis B, and HPV vaccines also declined. While some vaccination numbers are ticking up again, “action is urgently needed to address immunity gaps caused by pandemic-related disruptions in immunization delivery to prevent vaccine-preventable disease outbreaks in countries with health systems already burdened by Covid-19,” the researchers write:
The above is the estimated number of zero-dose children during the first year of life and estimated coverage with first dose of diphtheria and tetanus toxoids and pertussis-containing vaccine, by WHO region, worldwide, 2010, 2019, and 2020. AFR = African Region; AMR = Region of the Americas; DTP1 = first dose of diphtheria and tetanus toxoids and pertussis-containing vaccine; EMR = Eastern Mediterranean Region; EUR = European Region; SEAR = South-East Asia Region; WPR = Western Pacific Region:
Among tool kits to combat the COVID-19 school closures are one of the most frequent non-pharmaceutical interventions. However, school closures bring about substantial costs, such as learning loss. To date, studies have not reached a consensus about the effectiveness of these policies at mitigating community transmission, partly because they lack rigorous causal inference. Here we assess the causal effect of school closures in Japan on reducing the spread of COVID-19 in spring 2020. By matching each municipality with open schools to a municipality with closed schools that is the most similar in terms of potential confounders, a group can estimate how many cases the municipality with open schools would have had if it had closed its schools. They do not find any evidence that school closures in Japan reduced the spread of COVID-19. Their null results suggest that policies on school closures should be re-examined given the potential negative consequences for children and parents:
Vaccination reduces but does not eliminate the risk of covid-19 transmission within households, a study shows. It showed that one in four vaccinated household contacts of a covid-19 positive case became infected compared with 38% of unvaccinated contacts. Transmission depends not only on the susceptibility of contacts but also on the infectivity of cases, and while vaccination reduced susceptibility of infection, it did not appear to reduce infectivity, the risk of transmission to vaccinated contacts was similar regardless of whether the index case was vaccinated or unvaccinated. The study followed 205 household contacts of people confirmed covid-19 positive for the delta variant by PCR tests and who experienced mild symptoms or were asymptomatic. Most household contacts (62%) had been doubly vaccinated, 19% had received one vaccine dose, and 19% were unvaccinated. Contacts provided swabs for PCR testing daily for 14-20 days. Some 53 of the 205 household contacts returned a positive PCR test during the study, including 31 of 126 who were doubly vaccinated (25%) and 15 of the 40 unvaccinated contacts (38%).
The median length of time since vaccination was 101 days among vaccinated contacts infected, compared with 64 days for uninfected contacts, which suggests that protection begins to wane earlier than expected. Asked whether boosters should be brought forward in light of the findings, Neil Ferguson, said, “Six months is an arbitrary cut-off. It was chosen because most of the early data from Israel on the effect of boosters involve that level of delay.” He added, “Biologically, there’s nothing to make us think the boosters will be any less effective if given after four months. It is for the Joint Committee on Vaccination and Immunisation to consider the data and the government to consider whether they want to accelerate the booster programme.” PCR data for some of the participants was used to model their daily viral load trajectories. This revealed that viral load declined more rapidly among vaccinated people compared with those who were unvaccinated, but that there appeared to be no difference in the peak viral load of vaccinated and unvaccinated people. “The most statistically significant data point is that vaccinated people certainly have a faster rate of viral decline,” said Ferguson, “so they may potentially be infectious for less time, but they don’t necessarily have any reduced peak of viral load. Most transmission probably happens around that peak of viral load, which is why we think we’re still seeing substantial transmission rates from vaccinated people, both to unvaccinated people and to other vaccinated people.”
Ajit Lalvani Prof of Infectious Diseases said the faster rate of decline in viral load in vaccinated people helped explain why they get fewer symptoms, quicker resolution of symptoms, and crucially have much lower risk of developing severe disease. The modelling showed, however, that vaccination did not affect the time people spent “in the window of highest infectiousness” during peak viral load, and only partially prevented transmission of the delta variant, he added. “This means that unvaccinated people cannot therefore rely on the immunity of the vaccinated population for protection, they remain susceptible to infection, and risk of serious illness and death”:
As previously mentioned, on 20 October 2021, the UK government announced the acquisition of substantial doses of two new oral antiviral treatments for SARS-CoV-2: 480,000 courses of Merck’s molnupiravir and 250,000 courses of Pfizer’s PF-07321332+ritonavir.
Molnupiravir, is a prodrug of ß-D-N4-hydroxycytidine, which acts as a competitive nucleoside analogue in viral RNA dependent RNA polymerase, causing multiple non-sense mutations. The Move-Out placebo controlled trial in over 170 sites across Latin America, Europe, and Africa evaluated the efficacy of 800 mg molnupiravir twice daily for five days given within five days of the onset of mild or moderate covid-19 to non-hospitalised adults with at least one risk factor for severe disease. An earlier trial (Move-In) of molnupiravir in hospital inpatients was discontinued because of lack of efficacy, so Move-Out’s inclusion criteria were modified to focus on early disease (symptom onset criterion reduced from ≤7 to ≤5 days) and to include only people with risk factors for severe covid-19. Move-Out was halted by its data monitoring committee after an interim analysis (n=775) showed that molnupiravir reduced the risk of hospital admission or death from 14.1% to 7.3% (relative risk 0.55, 95% confidence interval 0.36 to 0.85, number needed to treat=15). In a previous phase II trial, the same regimen of molnupiravir reduced the isolation of infectious virus on day 3 from 16.7% to 1.9% of participants (P=0.02), while safety events were comparable between the molnupiravir and placebo arms.
Far less data are available for Pfizer’s SARS-CoV-2 protease inhibitor PF-07321332, either alone or in combination with low dose ritonavir. Ritonavir, which has an established safety profile, is commonly administered with other protease inhibitors as part of highly active antiretroviral therapy for HIV, as it inhibits hepatic metabolism of the partner drug. A phase I study of PF-07321332+ritonavir was completed in mid-2021 but results have not yet been published. Phase II and III trials are currently underway, including in high-risk outpatients with symptomatic covid-19 (n=3000, expected primary completion December 2021), low risk outpatients with symptomatic covid-19 (n=1140, expected October 2021), and a trial evaluating PF-07321332+ritonavir for post-exposure prophylaxis (n=2634, expected December 2021).
Limited trial data are available for both molnupiravir and PF-07321332+ritonavir. Although the recent Merck press release on molnupiravir is encouraging, full results from the phase III trial have not yet been made available. Questions remain about the nature of adverse events and efficacy in the context of vaccination and other treatments for covid-19. Of even greater concern, there are no publicly available safety or efficacy data for PF-07321332+ritonavir. Neither molnupiravir nor PF-07321332+ritonavir has been approved for covid-19 by any national medicines regulatory agency, although Merck has submitted an application for emergency use authorisation to the FDA and has begun a rolling review with the European Medicines Agency.
The introduction of new medicines for the prevention or treatment of covid-19 in an already strained healthcare system creates substantial complexity, especially in primary care. Ronapreve (casirivimab-imdevimab), a combination of two monoclonal antibodies for the prevention and treatment of covid-19, was introduced to UK hospitals only in September 2021 and is still not available for outpatients. It remains unclear how the administration of oral antivirals for covid-19 will fit into current pathways.
In the context of persistently high morbidity and mortality attributable to covid-19, effective antivirals have an obvious appeal. Reduced viral load would lessen the severity and duration of disease, as well as the risk of transmitting the virus. However, this appeal must not cloud objective and transparent decision making in which the available evidence, resources, and clinical landscape are fully considered with decisions aimed at optimising patient care at a population level. The costs of molnupiravir and PF-07321332+ritonavir have not been publicly disclosed. Furthermore, use of antiviral monotherapies for other viruses has led to the development of resistance.
The covid-19 antivirals taskforce was set up with the overly ambitious goal of delivering two antivirals against SARS-CoV-2 by autumn. The UK government’s decision to acquire molnupiravir and PF-07321332+ritonavir in the absence of sufficient evidence of safety and efficacy raises serious concerns about further mistakes being made in an attempt to fulfil this impossible task:
Next, many are upset and frustrated that decades of work in diagnosing, treating and researching tuberculosis (TB) have massively stalled. The slowdown means the world is losing ground against a disease that kills 1.5 million people every year. As the International Union Against Tuberculosis and Lung Disease held its annual conference online last week, Guy Marks, the union’s president, spoke for many when, comparing efforts against COVID-19, he said: “Many of us who work in the [TB] field feel robbed that equivalent efforts to develop a TB vaccine have never been as well committed or funded.” Marks added: “The failure to deliver COVID-19 vaccines to low- and middle-income countries and end tuberculosis are two sides of the same coin, a devaluation of human life in poor countries.” He has a point. But it doesn’t need to be this way.
Researchers are again urging decision-makers to revive diagnosis, treatment and research programmes for TB and other infectious diseases, such as malaria. And they are saying that much can be learnt from how the creation of COVID-19 vaccines was fast-tracked. Researchers have been warning that even more people will die from TB and other infectious diseases, such as malaria and HIV, if health systems continue to neglect these infections because of the continuing focus on coronavirus. And they are pleading with funders and governments not to drop the ball on TB work.
But their warnings are not being heeded. Not only are more people dying of the disease, but a target to reduce deaths by 90% from 2015 levels by 2030, part of the United Nations Sustainable Development Goals, is now in peril. According to research published this month, this failure will also lead to profound economic and health losses in the trillions of dollars, with the greatest impact in sub-Saharan Africa. A crucial problem is that fewer medical professionals have been available to diagnose and treat TB. As a result, the number of people diagnosed with the disease fell from 7.1 million in 2019 to 5.8 million in 2020. India, Indonesia and the Philippines are the most affected countries, according to the WHO’s latest TB report, published this month.
At the same time, funding has also shrunk. In 2019, funding for TB research totalled only <$1bn. By contrast, the NIH alone has set aside $5 billion for research on COVID-19. Published research in TB seems to be holding up for now, according to an analysis published this week in Nature Index. Some conference delegates spoke of lowering the targets for diagnosing and treating TB (and for other infectious diseases) to account for these and other ground realities. But that would be inadvisable. Although the COVID-19 pandemic is the highest priority for political leaders, wealthier nations and philanthropic donors, the pandemic has also shown how it is possible to boost both research into an infectious disease and treatment — and to do so at speed, which has led to COVID-19 vaccines in record time.
Lessons from COVID-19 must be applied to the fight against TB and other infectious diseases — from extraordinary resource mobilization to the use of emerging technologies, such as messenger RNA and other platforms to create vaccines. Advances in rapid and reliable diagnostics, advanced computation, sequencing and clinical-trial capacity for new vaccines and treatments can all be harnessed for TB and other infectious diseases. The TB vaccine in use today is essentially the same as the Bacillus Calmette-Guérin (BCG) vaccine introduced in July 1921. The COVID-19 pandemic has shown that it’s possible to produce new vaccines in one year, not 100, provided that there is funding and political will:
Most cases of SARS-CoV-2 infection are mild, but a proportion of people progress to severe COVID-19 for reasons that are not entirely clear. Some factors associated with the severe illness are known. For example, people with severe COVID-19 often have other pre-existing conditions, such as coronary artery disease, hypertension and diabetes. Unsurprisingly, compromised antiviral defences can also lead to life-threatening illness, as is the case for around 15% of people with severe COVID-19 who have a deficiency in what is called the type I interferon pathway. Indeed, it has been known since the discovery of this pathway in 1957 that it directly interferes with viral replication in an infected cell. There might also be other mechanisms at play in antiviral defences, such as a role for the natural killer (NK) cells of the immune system. Researchers now report that people with severe COVID-19 have higher than normal levels of an anti-inflammatory molecule, transforming growth factor-β1 (TGF‑β1), in their bloodstream, and that this is associated with impaired antiviral defence by NK cells and defective immune-system control of SARS‑CoV-2:
A large clinical trial found that a common and cheap antidepressant medication called fluvoxamine lowered the chances that high-risk Covid-19 patients would be hospitalized. The study found that among nearly 1,500 Covid patients in Brazil who were given either fluvoxamine or a placebo, the drug reduced the need for hospitalization or prolonged medical observation by one-third. The New York Times writes, “Some patients struggled to tolerate the drug and stopped taking it, the study said, raising a question among outside scientists about whether they had yet identified the ideal dose. But among those who had largely followed doctors’ orders, the benefits were even more striking. In those patients, the drug reduced the need for hospitalization by two-thirds and slashed the risk of dying: One Covid patient given fluvoxamine died, compared with 12 given a placebo.” Most patients in the study were unvaccinated and it’s unclear how well the drug would work in people who are vaccinated. Fluvoxamine is already approved for treating O.C.D in the U.S. so doctors can prescribe it “off label” to treat Covid.
Fluvoxamine is a selective serotonin reuptake inhibitor commonly indicated for the management of depression, obsessive-compulsive disorders, and other mental-health conditions. Owing to potential anti-inflammatory effects observed in initial experimental non-clinical studies, fluvoxamine has been proposed as a potential therapy for COVID-19. Accordingly, observational evidence has suggested favourable results of fluvoxamine with respect to symptom resolution and hospitalisations at 14 days. In trial results published in 2020, 152 outpatients with mild COVID-19 were randomly assigned to receive 100 mg fluvoxamine three times daily or matching placebo for 15 days.
The primary outcome was clinical deterioration, defined as shortness of breath or hospitalisation for shortness of breath or pneumonia, and oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. Within 15 days, none of the participants who received fluvoxamine and 8·3% of those who received placebo reached the primary endpoint (absolute risk difference 8·7%). Despite the promising results, limitations such as low statistical power and missing data for the primary outcome precluded definitive conclusions about the efficacy of fluvoxamine for the treatment of COVID-19. Researchers now report the results of TOGETHER, a randomised, adaptive, platform, placebo-controlled trial.
A total of 1497 participants were randomly allocated to fluvoxamine, 100 mg twice daily, or matching placebo. All included participants had a positive test for SARS-CoV-2 and known risk factors for disease progression (including age ≥50 years, diabetes, hypertension, obesity, smoking, conditions associated with immunosuppression, unvaccinated status, or comorbidities such cancer, cardiovascular, pulmonary, and kidney disorders). Enrolment occurred in 11 cities in Brazil. The primary endpoint was a composite of COVID-19 emergency setting retention for greater than 6 h or hospitalisation (defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital) from COVID-19 up to 28 days. Using a Bayesian analytical approach, the authors found that the proportion of patients reaching the primary endpoint was lower for the fluvoxamine group compared with placebo (11% vs 16%; relative risk: 0·68), with a probability of superiority of 99·8%.
The TOGETHER trial had low risk of bias. The allocation was concealed, participants, investigators, and caregivers were unaware of treatment assignments, and the main analyses followed the intention-to-treat principle. It should also be noted that TOGETHER constitutes the largest randomised trial completed to date aimed at testing the effect of fluvoxamine for outpatients with COVID-19. Conversely, the main study limitations are related to the lack of event adjudication and to the inconclusive effects on patient-important outcomes such as hospitalisation and mortality.
What are the lessons learned from the TOGETHER trial? From a research perspective, the TOGETHER trial reinforces the concept that it is possible to rapidly generate high-quality, randomised evidence even during a pandemic such as COVID-19. Undeniably, key factors for the success of this initiative rely on the scientific exchange between academic groups from Brazil and Canada and on the use of an adaptive, platform, randomised design. This research methodology allows simultaneous and efficient assessment of different potential therapies for COVID-19. From a clinical practice perspective, the results represent an important step in understanding the role of fluvoxamine for outpatients with COVID-19. In this sense, the study strongly suggests that fluvoxamine constitutes an effective, safe, inexpensive, and relatively well tolerated option for the management of ambulatory patients with COVID-19, which is particularly useful for (but not limited to) low-resource settings.
Despite the important findings from the TOGETHER trial, some questions related to the efficacy and safety of fluvoxamine for patients with COVID-19 remain open. The definitive answer regarding the effects of fluvoxamine on individual outcomes such as mortality and hospitalisations still need addressing. In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme. Finally, it is still unclear whether the results from the TOGETHER trial extend to other outpatient populations with COVID-19, including those without risk factors for disease progression, those who are fully vaccinated, and those infected with the delta variant or other variants:
Natural killer cells are white blood cells that are part of the innate branch of the immune system. They make key contributions to tackling viral infections, and their rapid activation is linked to the efficient control of several types of virus. NK cells can eliminate virus-infected cells in various ways, by releasing cytotoxic granules (termed degranulation) that directly kill the virus-infected cells, or by shaping both the innate and adaptive branches of immune defence by producing molecules called cytokines and chemokines, which can modulate the behaviour of other immune cells. Previous studies monitored the responses of NK cells in individuals with COVID-19 and reported lower than normal levels of NK cells in people with the disease, but the precise role of these cells in severe COVID-19 was unclear.
They analysed clinical samples and found a correlation between a rapid decline in the level of virus (the viral load) and high levels of NK cells in the bloodstream at the beginning of the infection. This correlation was not observed for the T cells or B cells of the immune system. The drastic decrease in NK cells in the bloodstream over the course of infection might be due to their death by a process called apoptosis, or their recruitment from the bloodstream to the lungs.
Crucially, they report that NK cells from healthy individuals can directly kill SARS-CoV-2-infected cells in vitro, but that NK cells from people with moderate or severe COVID-19 had impaired cell-killing activity (Figure below). These defective NK cells express higher-than-normal levels of the cytotoxic molecules that kill cells but are impaired in their ability to bind to target cells and to export their cytotoxic granules at the cell surface. In addition, NK cells from people with severe COVID-19 were less able to produce cytokines and chemokines than were such cells from healthy donors or from infected people who have no or minimal COVID-19 symptoms:
Figure. Characterising immune responses associated with COVID-19. Immune cells called natural killer (NK) cells can help to tackle viral infections by releasing cytotoxic granules that can kill infected cells. a, Previous work indicates that, in cases of mild COVID-19, NK cells express genes that are typically induced through the protein TNF-α pathway. This type of gene-expression profile arises through the action of transcription factors such as the protein NF-κB, and it aids the recovery of function of NK cells. b, They analysed samples of NK cells from individuals with severe COVID-19, and report that these cells had a gene-expression pattern characteristic of that driven by the protein TGF-β1. Gene expression mediated by this pathway depends on transcription factors that include Smad proteins. The authors report that NK cells from people with severe COVID-19 are impaired in their ability to bind to infected cells and to release cytotoxic granules. This finding provides insights into the factors driving severe COVID-19.
To dissect the mechanisms underlying the dysfunction of NK cells, they assessed gene expression by carrying out single-cell RNA sequencing of these cells from people with COVID-19 of differing degrees of severity. The authors found, consistently with another study reporting a similar transcriptional analysis of NK cells from people with COVID-19, that the cells had a gene-expression pattern characteristic of that driven by type I interferons. This gene-expression signature was more prominent in NK cells from people with severe rather than milder forms of COVID-19. Moreover, a pattern of gene expression characteristic of that driven by the protein TNF-α in NK cells has been described for mild cases of COVID-19. They also reveal an increase in the expression of genes controlled by TGF‑β1 in NK cells purified from either the blood or the lungs of people infected with SARS-CoV-2. This increase seems to correlate with the patients’ symptoms, with a higher prevalence of TGF‑β1-driven gene expression corresponding to more severe illness.
TGF-β1 is a cytokine with a central role in tissue remodelling, but it also suppresses the functioning of NK cells. TGF-β1 limits the ability of NK cells to control SARS-CoV-2 replication as tested in vitro. When NK cells from healthy individuals were treated with TGF-β1 in vitro, the cells were less able to form connections with infected target cells and were less able to degranulate and produce cytokines.
They report high levels of TGF-β1 in the blood of people with severe COVID-19, but not in those with no or minimal signs of the disease. Notably, the authors reveal that serum from people with severe COVID-19 can limit, to some extent, the in vitro degranulation and control of viral replication mediated by NK cells from healthy donors, and that this effect can be prevented by adding an antibody that blocks TGF-β1. Together, these findings indicate a correlation between severe COVID-19, the presence of a high level of TGF-β1 in the bloodstream and an impaired defensive response by NK cells.
Several questions remain. The first is whether NK cells are necessary to fight SARS‑CoV-2 infection. Several studies of mouse models of respiratory viral infections, such as influenza A virus, respiratory syncytial virus and Sendai virus, have shown that NK cells contribute to virus control and aid host survival5. Consistent with this, the only characteristic shared by people with various types of NK-cell deficiency is a predisposition to viral infections, especially of herpesvirus. The fact that type I interferons are strong activators of NK cells also suggests a link between deficiencies in type I interferons and impaired NK-cell-mediated antiviral immunity. All these findings, together with the inverse correlation between the number of functional NK cells and the severity of COVID-19, support a role for these cells in controlling SARS-CoV-2 infection, but formal proof of this hypothesis remains to be obtained.
A second question to be addressed is, what are the mechanisms underlying the high production of TGF-β1 during COVID-19? SARS‑CoV-2 contains a spike protein that interacts with the ACE2 receptor on human cells. This receptor is an enzyme that converts the protein angiotensin II (AngII) to a peptide called Ang1-7. The enzymatic activity of ACE2 is disturbed during SARS-CoV-2 infection, resulting in a rise in AngII levels that promotes TGF-β1 expression1. Thus, excessive damage to lung tissue caused by a high viral load might induce a high level of TGF-β1, which could affect NK cells. Moreover, TGF-β1 is known to promote a type of tissue damage called fibrosis, which is a hallmark of severe COVID-19. A rise in the level of AngII is a common feature of coronary artery disease, hypertension and diabetes, and high levels of TGF-β1 are observed in obesity. It will therefore be interesting to investigate whether the association of such conditions with severe COVID-19 involves defective functioning of NK cells mediated by TGF-β1.
Ways of manipulating NK cells are of increasing interest in anticancer therapy, using approaches such as immune-checkpoint inhibitors, NK-cell ‘engagers’ and off-the-shelf infusions of NK cells. The importance of NK cells in the control of viruses should similarly prompt the design of innovative treatments based on harnessing these cells to fight viral infections. In the case of severe COVID-19, the high levels of TGF-β1 present might compromise strategies to boost the activity of NK cells. Instead, the use of TGF-β1 blockers might be a way to promote NK-cell-mediated antiviral defence and prevent lung fibrosis, although the safety of such treatment in this context is a concern that should be addressed. In addition, monitoring TGF-β1 levels in plasma, along with TNF-α-mediated gene expression in NK cells from the bloodstream, might help to predict the outcome of infection and to guide a patient’s care appropriately:
With this in mind, researchers identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance: