Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study

‘COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness.

‘To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations.’

Read here (The Lancet, Nov 1, 2021)

View John Campbell’s video on “Severe illness after vaccination” on the above here.

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial

‘This is, to the best of our knowledge, the first large, randomised controlled trial to test the efficacy of fluvoxamine for acute treatment of COVID-19. We found a clinically important absolute risk reduction of 5·0%, and 32% RR reduction, on the primary outcome of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19, consequent on the administration of fluvoxamine for 10 days. This study is only the second study to show an important treatment benefit for a repurposed drug in the early treatment population.13 Our findings represent the complete analysis of the trial after the DSMC recommended stopping the active fluvoxamine group and all 28-day follow-up of randomly assigned patients. Given fluvoxamine's safety, tolerability, ease of use, low cost, and widespread availability, these findings might influence national and international guidelines on the clinical management of COVID-19.’

Read here (The Lancet, Oct 27, 2021)

Sinopharm vaccine for children: Some findings

‘Results from another study evaluating the Sinopharm SARS-CoV-2 vaccine in children were published on September 15 in The Lancet Infectious Diseases. The Phase 1/2 trial examined the safety and immunogenicity of the vaccine in a cohort of children aged 3-17 years, with participants broken into several age groups (3-5, 6-12, and 13-17 years) and dosing groups (0 [control], 2µg, 4µg, and 8µg). Three (3) doses of each vaccine dosage or placebo were administered 28 days apart. All adverse events were categorized as mild or moderate severity, but the article does not report on serious adverse events. The study concluded that children who received the vaccine had robust immune responses and similar levels of neutralizing antibodies to those observed in older vaccine recipients. The study recommended a 2-shot 4µg dose regimen for future Phase 3 trials. Additional data are being collected through a Phase 3 trial currently taking place in the UAE. 

Read here (The Lancet Infectious Disease, Sept 15, 2021)

Considerations in boosting Covid-19 vaccine immune responses

‘In an expert review published September 13 online in the peer-reviewed journal The Lancet, a group of US and international scientists claim current evidence does not support providing booster doses of SARS-CoV-2 vaccines to the general public. The group—including 2 departing US FDA officials and WHO experts—said that any decision to provide additional vaccine doses should be evidence-based, concluding that despite a small drop in protection against symptomatic disease caused by the Delta variant, authorized vaccine regimens continue to provide high levels of protection against severe disease and hospitalization for all major SARS-CoV-2 variants. The authors acknowledged that some additional doses might be needed immediately for certain elderly and immunocompromised populations, but they encouraged prioritizing primary immunizations over booster shots for the general public.

‘The authors also acknowledged that booster doses might be necessary in the future due to waning immunity or the emergence of a vaccine-resistant variant but that current evidence does not warrant additional doses now because “efficacy against severe disease remains high.” The authors noted that currently available vaccine doses could save more lives and provide better protection against the emergence of new SARS-CoV-2 variants if used in previously unvaccinated populations, especially those in low- and middle-income countries.’

Read here (The Lancet, Sept 13, 2021)

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol

‘Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females.’

Findings

‘55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age.’

Read here (The Lancet, August 5, 2021)

India's Covid-19 emergency: The Lancet proposes two strategies

‘India must now pursue a two-pronged strategy. First, the botched vaccination campaign must be rationalised and implemented with all due speed. There are two immediate bottlenecks to overcome: increasing vaccine supply (some of which should come from abroad) and setting up a distribution campaign that can cover not just urban but also rural and poorer citizens, who constitute more than 65% of the population (over 800 million people) but face a desperate scarcity of public health and primary care facilities. The government must work with local and primary health-care centres that know their communities and create an equitable distribution system for the vaccine.

‘Second, India must reduce SARS-CoV-2 transmission as much as possible while the vaccine is rolled out. As cases continue to mount, the government must publish accurate data in a timely manner, and forthrightly explain to the public what is happening and what is needed to bend the epidemic curve, including the possibility of a new federal lockdown. Genome sequencing needs to be expanded to better track, understand, and control emerging and more transmissible SARS-CoV-2 variants. Local governments have begun taking disease-containment measures, but the federal government has an essential role in explaining to the public the necessity of masking, social distancing, halting mass gatherings, voluntary quarantine, and testing. Modi's actions in attempting to stifle criticism and open discussion during the crisis are inexcusable.’

Read here (The Lancet, May 8, 2021)

Lancet report says Covid-19 is primarily airborne, safety protocol should change urgently

‘A report published in the journal The Lancet has dismissed the predominant scientific view that SARS-CoV-2, the coronavirus that causes Covid-19, is not an airborne pathogen. The authors of the report have listed 10 reasons for their claim that "SARS-CoV-2 is transmitted primarily by the airborne route".

‘The paper, written by six experts from the UK, the US and Canada, argues that there are "insufficient grounds for concluding that a pathogen is not airborne" while "the totality of scientific evidence indicates otherwise". The experts called for urgent modification in the Covid-19 safety protocol.’

Read here (India Today, Apr 16, 2021)

Ten scientific reasons in support of airborne transmission of SARS-CoV-2

Read here (The Lancet, April 15, 2021)

Covid-19 & neurological conditions

‘A study published in The Lancet Psychiatry estimates that more than one-third of COVID-19 survivors experienced neurological symptoms within 6 months of their infection. Researchers at the University of Oxford (UK) evaluated medical record data for nearly 250,000 COVID-19 patients and found that 33.62% were diagnosed with a neurological or psychiatric condition in the 6 months following their infection, including 12.84% for whom this was their first such diagnosis. The proportion increased among those who were admitted to an intensive care/treatment unit (ICU/ITU), up to 46.42% and 25.79%, respectively. The most common conditions included anxiety disorders (17.39%), mood disorders (13.66%), substance use disorder (6.58%), insomnia (5.42%), nerve disorders (2.85%), and ischemic stroke (2.10%). The study breaks down each condition by disease severity.’

Read here (The Lancet, April 6, 2021)

Read press release here

New Covid variants have changed the game, and vaccines will not be enough. Lancet Covid-19 Commission calls for global ‘maximum suppression’

‘Put simply, the game has changed, and a successful global rollout of current vaccines by itself is no longer a guarantee of victory... No one is truly safe from COVID-19 until everyone is safe. We are in a race against time to get global transmission rates low enough to prevent the emergence and spread of new variants. The danger is that variants will arise that can overcome the immunity conferred by vaccinations or prior infection.

‘What’s more, many countries lack the capacity to track emerging variants via genomic surveillance. This means the situation may be even more serious than it appears.

‘As members of the Lancet COVID-19 Commission Taskforce on Public Health, we call for urgent action in response to the new variants. These new variants mean we cannot rely on the vaccines alone to provide protection but must maintain strong public health measures to reduce the risk from these variants. At the same time, we need to accelerate the vaccine program in all countries in an equitable way. Together, these strategies will deliver “maximum suppression” of the virus.’

Read here (The Conversation, Apr 6, 2021)

Download report here (Lancet Covid-19 Commission Taskforce on Public Health,  March 2021)

Thromboembolism and the Oxford–AstraZeneca COVID-19 vaccine: Side-effect or coincidence?

‘When making decisions on the use of drugs based on pharmacovigilance, it is important to take into account the natural incidence of illnesses, such as venous thromboembolisms, that might be interpreted as serious adverse events. Here, based on pre-pandemic incidence rates from the entire Danish population, we report that the number of venous thromboembolisms reported in relation to the Oxford–AstraZeneca COVID-19 vaccine does not seem to be increased beyond the expected incidence rate. Nevertheless, recent reports of thrombocytopenia-associated cerebral venous sinus thrombosis, multiple thrombosis, and bleeding within a short timeframe after receipt of the vaccine are concerning and are receiving due attention from health authorities. On March 18, 2021, with reference to the Oxford–AstraZeneca COVID-19 vaccine, the EMA concluded that “benefits still outweigh the risks despite possible link to rare blood clots with low blood platelets”.’

Read here (The Lancet, Mar 30, 2021) 

Lancet editor says inequality and Covid-19 have converged to create a ‘syndemic’

‘In his new book "The COVID-19 Catastrophe: What's Gone Wrong and How to Stop It Happening Again," Dr. Richard Horton does more than trace the history of the COVID-19 pandemic and explain how we should listen to scientific experts in confronting this global scourge.

‘He does this, of course, but Horton is more ambitious than that. As editor-in-chief of "The Lancet" — one of the world's oldest, most famous and most prestigious medical journals — Horton has overseen the publication of countless articles on a variety of medical subjects. Hence, one can sense in his book a desire to apply the full breadth of his knowledge and experience to this problem. His conclusion is both fascinating and extremely relevant, even urgent.

‘As Horton explains, the COVID-19 pandemic was unnecessarily worsened by deeper social problems, from economic policies that left millions upon millions of people especially vulnerable to Western governments who made political assumptions about the virus that proved to be gravely mistaken. Speaking with Salon, Horton discussed everything from President Donald Trump's failure to address the pandemic (as well as President Joe Biden's early successes) to an intriguing thought experiment on what would have happened if the governments the world could have simply paid people to stay home.’

Read here (Salon, Feb 6, 2021)

Covid-19 and the convergence of nations

‘Few, if any [government], have set out recovery strategies that include the goal to reduce inequalities as part of future pandemic preparedness. Yet an essential truth of this emergency is that stronger security depends on fairer societies. But that is not the whole story...

‘In a working paper published last week by the US National Bureau of Economic Research, the Nobel economist Angus Deaton concludes that, at least in terms of global income, inequalities have decreased. He claims that the views of several respected authorities, ranging from fellow Nobel laureate Joseph Stiglitz to the UN Development Programme, are plain wrong. His argument is that high-income nations have suffered higher rates of mortality than low-income and middle-income countries. These higher mortality rates have translated into larger falls in wealth. This is an important observation...

‘The reality is that health and prosperity go hand-in-hand. During this pandemic, the smaller the number of deaths, the larger the income of a nation. The result has been that incomes per person in wealthier countries have fallen more than those in low-income countries. International income inequalities have therefore decreased. Nations have converged, not diverged. As Deaton notes, the pandemic “has brought countries closer together, not further apart”.

Read here (The Lancet, Feb 6, 2021)

Viral loads, including in asymptomatic cases, a key factor in transmission

‘The scientific community is still uncovering the full picture of SARS-CoV-2 transmission dynamics. A study published in The Lancet: Infectious Diseases analyzed SARS-CoV-2 transmission among clusters in Catalonia, Spain, to understand the relationship between viral load and transmission risk. The researchers utilized participant data from a previous clinical trial, and they identified 314 COVID-19 patients that met their inclusion criteria. Among those patients, 282 had at least 1 contact (753 total contacts). The index patients infected 125 secondary cases, corresponding to a secondary attack rate of 17%. 

‘The researchers identified a statistically significant association between viral load in the index patients and the subsequent secondary attack rate. Among index patients with the lowest viral load, index patients exhibited a secondary attack rate of 12%, compared to 24% among the highest group. The researchers estimate that the odds of secondary transmission increase 30% for every log(10) increase in viral load. Additionally, the study found increased likelihood that secondary cases would develop COVID-19 symptoms associated with increased viral load in the index patients (aHR of 1.12 per log(10) increase in viral load). While further research is needed to more fully characterize the factors associated with transmission, this study provides evidence that the index patient’s viral load could be a major driver of secondary transmission risk and potentially disease severity in secondary cases.’ (Source: Updates on the COVID-19 pandemic from the Johns Hopkins Center for Health Security.)

Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study

Read original here (The Lancet, Feb 2, 2021)

Sputnik V ‘91·6% efficacious, well tolerated’: Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia

‘Our interim results of the phase 3 Gam-COVID-Vac trial show that the vaccine is 91·6% (95% CI 85·6–95·2) efficacious against COVID-19 (from day 21 after first dose, the day of receiving second dose). Our results also showed that the vaccine was 100% (95% CI 94·4–100) efficacious against severe COVID-19, although this was a secondary outcome so the results are preliminary. The vaccine was well tolerated, with 45 (0·3%) of 16 427 participants in the vaccine group reporting serious adverse events, all of which were considered not related to the vaccine... 

‘The vaccine induced robust humoral (n=342) and cellular (n=44) immune responses in all age strata. Notably, there were a few non-responders in the vaccine group (six of 342), possibly due to immunosenescence in older people, individual characteristics of the formation of an immune response, or concomitant immunological disorders.’

Read here (The Lancet, Feb 2, 2021) 

Efficacy of the AstraZeneca-Oxford University vaccine: A preprint for The Lancet

‘A study (preprint for The Lancet) of data from the Phase 3 clinical trials of the AstraZeneca-Oxford University vaccine evaluated vaccine efficacy after a single dose and for alternate timing for the booster dose. Notably, the UK adapted the timing for the booster dose from 4 weeks after the first dose—which is how the vaccine was designed to be administered and the timing used for clinical trials—to 12 weeks in an effort to provide the first dose to as many people as possible. This study assessed the vaccine’s efficacy in participants who received the 2 doses between 4 and 12 weeks apart.

‘The researchers found that the efficacy after the first dose did not wane in the first 12 weeks. A single dose of the vaccine was 76% efficacious in preventing symptomatic COVID-19 disease in the first 90 days after vaccination, although it was associated with a substantial decrease in efficacy with respect to preventing asymptomatic infection. Notably, however, the additional asymptomatic infections could potentially be among participants who would have otherwise developed COVID-19 symptoms. Additionally, the efficacy in preventing symptomatic disease was higher in participants who received the booster dose later than in those who received it earlier. Vaccine efficacy was 82.4% among participants who received their booster dose 12 weeks or longer after the first dose, compared to 54.9% in those who received their 2 doses less than 6 weeks apart. These results provide support for vaccination plans that delay the booster dose beyond the intended 4 weeks, considering that the immunity conferred after the first dose appears to be relatively stable over the first several months and the overall protection appears to increase with an increased time between the prime and booster doses.

‘The researchers also found that vaccination was associated with an overall reduced risk of infection—54.9% efficacy for 2 doses and 67% efficacy for 1 dose—which provides evidence that the vaccine could also provide protection against SARS-CoV-2 transmission. The role of SARS-CoV-2 vaccines in mitigating transmission risk remains uncertain, but these findings provide a promising indication that vaccination could reduce community spread of the virus, which would be a major tool to bring the pandemic under control.’

**The above summary was contained in an update of Feb 5, 2021, on the COVID-19 pandemic from the Johns Hopkins Center for Health Security 

• Single dose administration, and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine

Read here (The Lancet, Feb 1, 2021)

Resurgence of Covid-19 in Manaus, Brazil, despite high seroprevalence

‘A study published in The Lancet analyzed the increased SARS-CoV-2 transmission in Manaus, Brazil, a region that had previously shown high levels of seroprevalence among its community members. A study conducted in October 2020 detected SARS-CoV-2 antibodies in samples from 76% of blood donors, which suggested that the region may have reached the threshold to provide some level of community immunity (ie, herd immunity). Despite the high seroprevalence, Manaus exhibited a large surge in COVID-19 cases and hospitalizations in January 2021.

‘The researchers present 4 possible explanations for the surprising surge in cases. First, the previous study could have overestimated the seroprevalence, which could have put the community below the herd immunity threshold. Second, immunity to SARS-CoV-2 conferred by earlier infection could have waned, resulting in re-infections. Third, the new infectious could be a result of emerging variants, including the P.1 variant first reported in the area, that are less susceptible to antibodies from prior infections. And finally, new SARS-CoV-2 lineages could simply be exhibiting much higher transmissibility, which could allow widespread community transmission even in areas with high existing seroprevalence. The researchers note that these theories are not mutually exclusive, and further study is needed to better characterize the factors driving the current resurgence. In particular, it is critical to investigate the potential that emerging variants could evade antibodies developed from infection with other strains, which could inform response activities in communities around the world.’ 

Read here (The Lancet, Jan 27, 2021)

The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe Covid-19: A pilot, double-blind, placebo-controlled, randomized clinical trial

Added value of this study: ‘This pilot, randomized, placebo-controlled, double blind trial failed to show a reduction in the proportion of PCR-positive patients seven days after ivermectin treatment; yet it shows a reduction in the self-reported anosmia/hyposmia and a (non-statistically significant) tendency to lower viral loads and lower IgG titers which presumably reflect milder disease.’

Implications of all the available evidence: ‘The positive signal found in this pilot together with emerging evidence from animal models and other clinical trials warrants the conduction of larger trials using ivermectin for the early treatment of COVID-19.’

Read here (EClinicalMedicine, The Lancet, Jan 19, 2021)

Vitamin D and Covid-19: Why the controversy?

‘The issue of vitamin D supplementation has been extensively debated, with strong arguments in favour and against. The COVID-19 pandemic has further escalated the discussion. It has long been clear that groups that traditionally exhibit vitamin D deficiency or insufficiency, such as older adults and nursing home residents, and Black, Asian, and minority ethnic populations, are the same groups that have also been disproportionately impacted by COVID-19. Additionally, increased time spent indoors due to strict lockdowns and shielding triggered concerns that some people might not obtain the necessary physiological levels of vitamin D from sunlight...

‘On Dec 17, 2020, the National Institute for Health and Care Excellence (NICE), in collaboration with Public Health England and the Scientific Advisory Committee on Nutrition, published an updated rapid review of recent studies on vitamin D and COVID-19. Their recommendations support the current government advice, revised in April, 2020, during the first lockdown in the UK, for everyone to take vitamin D supplements to maintain bone and muscle health during the autumn and winter months... However, the rapid review concluded that sufficient evidence to support vitamin D supplementation with the aim of preventing or treating COVID-19 was still lacking and that the topic should be further investigated. Experts studying vitamin D welcomed the call for more research, but the lack of specific recommendations in the context of COVID-19 was also met with disappointment by many in the scientific community who have argued that vitamin D supplementation is generally safe and that any potential low toxicity would likely be strongly outweighed by any potential benefits in relation to protection from COVID-19.

‘NICE should continue to monitor new evidence as it is peer-reviewed and published, including results from several clinical trials on vitamin D and COVID-19 outcomes that are currently underway. However, particularly in countries where the pandemic situation continues to worsen (and will continue to do so during the winter months before the effects of vaccinations become perceptible), additional evidence could come in just too late. In an ideal world, all health decisions would be made based on overwhelming evidence, but a time of crisis may call for a slightly different set of rules.’ [blog editor’s emphasis]

Read here (The Lancet, Jan 11, 2021)

Prevalence and risk factors for delirium in critically ill patients with Covid-19: A multicentre cohort study

‘In this large, international cohort study of more than 2000 patients with severe COVID-19, acute brain dysfunction (coma or delirium) was more common and more prolonged than observed in other studies of patients with acute respiratory failure without COVID-19. Patients with COVID-19 also received treatment with sedatives for a prolonged duration: two-thirds of patients were given benzodiazepines and propofol for a median of 7 days. 

‘As a result of the COVID-19 pandemic, many ICUs were operating in resource-constrained environments, and despite demonstrated efficacy in previous studies, evidenced-based strategies, such as light sedation techniques, spontaneous awakening and breathing trials, avoiding benzodiazepines, early mobility, and family visitation, all occurred on fewer than 1 in every 3 days among patients with severe COVID-19. We found that risk of delirium among patients with severe COVID-19 was lower when benzodiazepine sedative infusions were avoided and family was present, whereas greater severity of illness and greater respiratory support was associated with a higher risk of delirium.’

Read here (The Lancet, Jan 8, 2021)

Long Covid guidelines need to reflect lived experience

‘Since May, 2020, increasing attention has been given to the experiences of people with COVID-19 whose symptoms persist for 4 or more weeks. According to the Office for National Statistics (ONS), an estimated 186 000 people (95% CI 153 000–221 000) in private households in England currently have COVID-19 symptoms 5–12 weeks or longer after acute infection. The ONS estimate that one in five people have symptoms that persist after 5 weeks, and one in ten have symptoms for 12 weeks or longer after acute COVID-19 infection. Research on long COVID is growing, including into the underlying pathology, consequences, and sequelae, as well as rehabilitation for patients. Evidence suggests that a considerable proportion of people with long COVID have severe complications. We have lived experiences of long COVID, with a range of symptoms lasting for more than 6 months...

‘Guidelines must represent the complexity of long COVID, including the areas where evidence is still emerging. Hasty attempts to rename the condition or compare it to other conditions is a disservice to thousands of people, and could result in missed pathology to the detriment of the patient. Comprehensive long COVID guidelines are essential to prevent an epidemic of long-term, chronic disease as a result of early mismanagement of pathology, and the potential implications of such an epidemic for health systems and economies.’

Read here (The Lancet, Dec 21, 2020)