A COVID prophylactic cocktail of long-acting antibodies cut the risk of developing symptomatic disease in a high-risk unvaccinated patient population, AstraZeneca announced on Friday.
Initial phase III trial data showed that AZD7442 (tixagevimab and cilgavimab) as pre-exposure prophylaxis significantly reduced the risk of developing COVID symptoms by 77% versus placebo, meeting the trial’s primary endpoint. AstraZeneca further noted there were no cases of severe COVID or COVID-related deaths in the intervention group, while there were three cases of severe COVID and two deaths in the placebo group.
No safety concerns were noted by the manufacturer, as the treatment was well-tolerated and adverse events were balanced between groups.
A key feature of the trial was that 75% of participants had comorbidities, including being “at risk of an inadequate response to active [immunisation],” such as older adults and those with immunosuppressive disease or on immunosuppressive medication.
“With these exciting results, AZD7442 could be an important tool in our arsenal to help people who may need more than a vaccine to return to their normal lives,” the trial’s principal investigator, Myron Levin, MD, of the University of Colorado School of Medicine, said in a statement.
AZD7442 was derived from the B cells of convalescent patients. PROVENT was a phase III randomised trial conducted in the US and Europe. Participants were 5197 adults “who would benefit from prevention” with the long-acting antibody, were unvaccinated at the time of enrollment, and tested negative for SARS-CoV-2. Participants were randomised 2:1 to receive a single 300 mg dose of AZD7442 or placebo. AstraZeneca noted that 43% of participants were ages 60 and older. The company noted that the drug is active in lab studies against emerging strains, including the Delta variant.
Patients were followed for 183 days, though subjects are slated to be followed for 15 months, AstraZeneca said. Data will be submitted for peer-reviewed publication while the company seeks approval for AZD7442.
A study found that antibiotic prescriptions for non-respiratory ailments were unchanged by COVID lockdown in Australia, which had comparatively few COVID cases.
In regions with high levels of COVID transmission, such as Europe and the United States, prescriptions for antibiotics in the community fell dramatically after COVID restrictions were introduced in early 2020. A study published in the British Journal of Clinical Pharmacology looked at antibiotic prescribing in Australia, which has so far had low COVID rates.
Analysing national claims data, researchers observed that COVID restrictions in Australia were associated with substantial reductions in community dispensing of antibiotics primarily used to treat respiratory infections, but found that antibiotics for non-respiratory infections did not change.
“The issue is that antibiotics should rarely be prescribed for common viral respiratory infections in the first place. These big reductions show how low general practitioners’ antibiotic prescribing could go if guidelines were followed more closely,” said co–senior Helga Zoega, PhD, of UNSW Sydney, in Australia.
In the UK’s first wave, more than one in ten COVID hospitalised patients acquired the disease in a hospital according to researchers conducting the world’s largest study of severe COVID.
Dr Jonathan Read from Lancaster University with colleagues from other UK universities led the research into hospital-acquired infections (HAIs) which was published in The Lancet.
For the study, researchers analysed records of COVID patients in UK hospitals enrolled in the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) Clinical Characterisation Protocol UK (CCP-UK) study, who became ill before 1st August 2020.
The researchers found that at least 11.1% of COVID patients in 314 UK hospitals were infected after admission. The proportion of hospital-acquired infections also rose to between 16% and 20% in mid-May 2020, well after the first wave’s peak in admissions.
“We estimate between 5699 and 11 862 patients admitted in the first wave were infected during their stay in hospital. This is, unfortunately, likely to be an underestimate, as we did not include patients who may have been infected but discharged before they could be diagnosed,” the researchers said.
“Controlling viruses like SARS-CoV-2 has been difficult in the past, so the situation could have been much worse. However, infection control should remain a priority in hospitals and care facilities,” said Dr Read.
Dr Chris Green, University of Birmingham, said: “There are likely to be a number of reasons why many patients were infected in these care settings. These include the large numbers of patients admitted to hospitals with limited facilities for case isolation, limited access to rapid and reliable diagnostic testing in the early stages of the outbreak, the challenges around access to and best use of PPE, our understanding of when patients are most infectious in their illness, some misclassification of cases due to presentation with atypical symptoms, and an under-appreciation of the role of airborne transmission.”
According to the type of care provided, there were notable differences in infections. Lower proportions of hospital-acquired infection were seen in hospitals providing acute and general care (9.7%) than residential community care hospitals (61.9%) and mental health hospitals (67.5%). Professor Calum Semple, University of Liverpool, said: “The reasons for the variation between settings that provide the same type of care requires urgent investigation to identify and promote best infection control practice. Research has now been commissioned to find out what was done well and what lessons need to be learned to improve patient safety.”
In a digital media briefing, Western Cape Premiere Alan Winde said that the province had still not exited its third wave of COVID infections.
With an R value of 0.9, this was the first time in the third wave that the value was below 1. However, this could be due to testing delays caused by the long weekend. Indeed, a sharp daily increase in national COVID cases has been recorded as of Thursday’s latest data, with the NICD reporting a 90% jump to 14 271. Overall case positivity still hovers above the 20% mark at 22.52%.
Cases continue to spike While overall cases in the Western Cape are plateauing, spikes in certain areas are seeing higher case rates than in the peak of the second wave. Oxygen is still being used as fast as it can be produced in the province, being supplemented by an additional 22 tonnes per day by truck deliveries from other provinces. A total of 3665 patients are in acute hospitals, with 99% occupancy in Metro areas. The Metro area is seeing a week-on-week case rise of 7%, which points to a plateau.
Vaccines proving effective – even against beta The Johnson & Johnson vaccine however is proving effective, with 91-95% protection against death and 65-66% protection against hospitalisation. With regard to variants, the vaccine confers 67% protection against hospitalisation when beta is dominant and 71% where delta is dominant.
The Western Cape’s vaccination programme remains on track, with 287 000 doses of Pfizer and 28 800 J&J doses to arrive today, Friday 13th.
Elsewhere, with 31.2 new cases per 100 000 people, KwaZulu-Natal may be becoming a COVID hotspot.
A further 473 people have died from COVID, bringing the official death toll to 76 247.
In an article published in the South African Medical Journal, Shabir Madhi, Professor of Vaccinology at Wits, argues that COVID variants have made the initial goal of attaining herd immunity no longer feasible, even for well-resourced countries. However, vaccine protection against severe COVID seems a more realistic path to normalcy.
In low and middle income countries (LMICs), the official COVID case estimates are likely grossly underestimated, Prof Madhi writes, due to a lack of testing coverage. Even in South Africa, the true number of COVID cases is likely in the region of 10 times the 2.39 million recorded through testing. The true number of COVID-related deaths in India is also estimated as 3.4–3.9 million, again 10 times the official count, and in South Africa it is likely three times the official figure of 70 388 in July 2021.
While New Zealand researchers have suggested that COVID eradication is feasible, it is likely a very long term goal if at all attainable. The herd immunity goal can be considered with the equation (p1 = 1 – 1/R0), where p1 is the proportion of immune individuals who will also no longer transmit the virus, and R0 is the reproduction rate, ie the number of susceptible individuals a single infected person can further infect. However, this ignores key aspects of the virus.
The problem is that the proportion of people that would need to be immunised to achieve herd immunity was initially calculated at 67%, based on an assumed R0 of 3, derived from the Wuhan strain’s R0 of 2.5 to 4. However, the Delta variant has an R0 of 6, meaning that to reach herd immunity, 84% of the population would need to be vaccinated. In South Africa, this would be 100% of the population aged over 12.
The emergence of SARS-CoV-2 variants, especially the Beta variant with the E484K mutation, showed that existing vaccine protection, including the Pfizer variant, can be degraded to an extent.
Studies have strongly suggested that neutralising and antibody titers are associated with mild to moderate COVID protection, while protection from severe COVID may be mediated by T-cell immunity.
Real world data showed that in Israel, with a world best immunisation of 61.6% using the Pfizer vaccine which produces the greatest antibody response, herd immunity appeared to be successful until an outbreak of the more transmissible Delta variant combined with waning vaccine effectiveness.
However, in the UK, excess death data showed that, even with a resurgence of cases caused by the Delta variant, there was a significant decoupling of deaths from cases. This points to the effectiveness of vaccines in preventing severe illness, as opposed to reaching herd immunity.
Vaccine rollouts have therefore not interrupted COVID transmission. Prof Madhi concludes that, based on an estimated R0 of 6 for the Delta variant, “it is unlikely that any country could have a sustainable strategy for durable high level of protection against infection by the delta variant. Mutations of the SARS-CoV-2 genome are likely to continue resulting in enhanced transmissibility, infectiousness and resistance to neutralising activity.”
He observes that the “UK approach seemingly concedes that the goal of herd immunity, even in a highly resourced setting, is unattainable.”
He adds that aspiring to reach herd immunity by wealthy countries comes at the cost of exacerbating vaccine inequality, which he says “is immoral.” Antibody dynamics modelling suggests that a booster would be required every 2–3 years to protect against severe COVID, and every 6–9 months to protect against moderate disease. This is a challenging goal, and likely unattainable for most LMICs, especially given the slow rate of vaccination in those settings.
A new analysis shows that the global eradication of COVID is tough but theoretically more feasible than for polio and less so than it was for smallpox.
The article in BMJ Global Healthranked the feasibility of eradicating the three diseases based on technical, socio-political and economic factors.
Smallpox, which was declared eradicated in 1980, had the highest average score for eradication feasibility. It had an average score of 2.7 on a three-point scale across 17 variables. COVID had an average score of 1.6 which was close to polio’s average score of 1.5.
Professor Nick Wilson from the University of Otago said that their analysis shows COVID’s eradication is feasible.
Vaccination programmes, public health measures and the global interest in combating the disease together contribute to making eradication possible.
“Elimination of COVID-19 at the country level has been achieved and sustained for long periods in various parts of the Asia Pacific region, which suggests that global eradication is possible.”
Vaccination programmes eradicated smallpox and two of the three serotypes of poliovirus, while other diseases are close to eradication. China recently became the 40th country to be certified malaria-free.
In ranking the feasibility of eradication for the three diseases, the researchers incorporated factors including the availability of safe and effective vaccines, the possibility of lifelong immunity, the impact of public health measures, effective infection control messaging by governments, political and public concern about the infection and public acceptance of infection control measures.
While there has been a focus on the need to reach herd immunity to overcome COVID, population immunity may not be essential to combat the disease, as smallpox was eradicated through ring-vaccination programmes which target the contacts of those infected.
The challenges of eradicating COVID relative to smallpox and polio include poor vaccine acceptance in some countries and the emergence of variants of the pandemic virus that may be more transmissible or able to evade the protection from vaccines.
But Professor Wilson said eventually the virus will be reach the limit of more infectious mutations, and so new vaccines will likely be formulated to deal with evolving strains of the disease.
Other obstacles includedthe cost of global vaccination and upgrading health systems, and achieving international cooperation in the face of aggressive anti-science movements and vaccine nationalism.
Professor Wilson says while the virus may infect animal populations, they will note likely hamper eradication.
“Wild animal infections with SARS-CoV-2 appear to be fairly rare to date and when companion animals become infected, they don’t appear to reinfect humans.”
A co-author of the article, Professor Michael Baker from the University’s Department of Public Health, says global concern about the pandemic could be tapped.
“The massive scale of the health, social and economic impacts of COVID-19 in most of the world has generated unprecedented global interest in disease control and massive investment in vaccination programmes.
“Unlike smallpox and polio, control of COVID-19 also benefits from the added impact of public health measures, such as border controls, social distancing, contact tracing and mask wearing, which can be very effective if well deployed.”
Professor Baker says upgrading health systems to target COVID-19 could also help to control other diseases, and could even aid in eradicating measles.
“When all factors are taken into account, it could be that the benefits of eradicating COVID-19 outweigh the costs, even if eradication takes many years and has a significant risk of failure.”
This work is preliminary, the researchers cautioned.
“The World Health Organization or a coalition of national agencies working collaboratively needs to formally review the feasibility and desirability of attempting COVID-19 eradication on a global basis,” Professor Baker says.
The researchers noted it is important to distinguish between eradication of infection, ie the permanent reduction to zero of the worldwide incidence of infection caused by a specific agent as a result of deliberate efforts; and elimination, ie the reduction to zero of the incidence of infection caused by a specific agent in a defined geographical area as a result of deliberate efforts.
COVID elimination has been reached and sustained for long periods in a number of jurisdictions in the Asia-Pacific region (notably China, Hong Kong, Taiwan, Australia and New Zealand), demonstrating that global eradication is technically possible.
Infected cell covered with SARS-CoV-2 viruses. Source: NIAID
In a small study, people with previous COVID infection were observed to have higher antibody levels after a single dose of Pfizer vaccine compared with uninfected people after two doses.
Furthermore, there was no increase in IgG levels after the second dose among those previously infected, possibly indicating that one dose of vaccine may be sufficient for this population, reported James Moy, MD, of Rush University Medical Center in Chicago, and colleagues in aJAMA Network Openresearch letter.
“This study highlights the potential for recommending a single dose for previously infected individuals and may be useful for discussions surrounding vaccination strategy,” the authors wrote.
Whether to offer only a single dose of vaccine to those previously infected with COVID is a hot topic, with some experts conceding that previously infected individuals likely only need one dose, but would be challenging to implement.
Indeed, Dr Moy’s group urged performing “baseline serological testing” for previously infected individuals, but CDC and the agency’s Advisory Committee on Immunization Practices (ACIP) argued that this would be next to impossible to do for the entire country.
At a meeting in March, ACIP Chair José Romero, MD, voiced concern that the one-dose strategy would only work if individuals had sufficiently high antibody titers. If people had no or low antibodies, they may not have “enough memory B-cells to boost to levels that will be protective,” he said.
The researchers recruited adult participants at the team’s academic medical center, sorting them according toinfection status. Prior infection was established by a positive RT-PCR test and/or a positive SARS-CoV-2 antibody result. Overall, 30 participants had no evidence of infection, while 29 did.
The authors measured SARS-CoV-2 spike IgG levels at baseline and then after the first and second doses of the Pfizer vaccine among all participants.
There were no significant IgG differences between the first and second dose in previously infected individuals. Interestingly, four participants reported a previous positive COVID test via RT-PCR, but had no evidence of antibodies.
“Vaccine responses in these four participants resembled infection-naive individuals,” Moy’s group noted, adding that because this group did not develop S-protein antibodies, baseline testing should be required before forgoing a second dose.
The researchers said study limitations included the small sample size and lack of diversity of participants, as well as lack of neutralisation studies and T-cell response studies.
An 11-month-old girl in Houston, Texas, had to be airlifted to a hospital in a different city because no paediatric hospitals in Houston would accept her as a transfer patient.
“She needed to be intubated immediately because she was having seizures,” said Patricia Darnauer, the administrator for LBJ Hospital. “We looked at all five major paediatric hospital groups and none [had beds] available.”
The little girl will be receiving treatment at Baylor Scott & White McLane Children’s Medical Center some 220 kilometres away.
The situation is sad but not surprising for Dr Christina Propst, who is one of the most outspoken pediatricians in Houston. Ever since the pandemic began in the US, Dr Propst has encouraged masking, social distancing, and being cautious to anyone who would listen.
“The emergency rooms at the major children’s hospitals here in Houston, the largest medical center in the world, are extremely crowded,” said Dr Propst. “They are filling, if not full, as are the hospitals and intensive care units.”
Delta variant infecting more children Dr Propst and other clinicians ascribed the scarcity of paediatric beds, to the delta variant of COVID noticeably affecting more children, as well as being more transmissible. Texas Children’s Hospital has 30 children and adolescents hospitalised with COVID, compared to their January peak of 40.
However, the problem is worsened by widespread cases of Respiratory Syncytial Virus (RSV) in children. This is all taking place during the summer break for US schools, where doctors are used to injuries from playing outdoors.
Darnauer spoke of high numbers of patients at her hospital. “We are back beyond our pre-pandemic volumes at LBJ.”
Dr Propst advises mask wearing for those children not old enough for the vaccine, and she would also like to see Texas once again allow public schools to mandate masks. Unlike many other countries, COVID health regulations are largely up to individual states.
“If children are not masking in schools, it will be a major problem,” said Dr Propst.
She added that, even in normal times, the start of the school year generally causes a lot of germs to spread.
“It is typical that two weeks after school we see a great surge of strep and other sources of infection. We are bracing ourselves, not a question of when, it will be bad,” she said.
Western Cape premier Alan Winde said that the province is at the peak of its third wave of COVID infections.
“We are beginning to see the flattening of the curve at our peak as new case infections start to plateau again,” he said in a briefing on Thursday. “This happened after an initial plateau two weeks ago, and then a subsequent increase the week thereafter.
“This is largely explained by a disruption in testing caused by the taxi violence in the Cape Metro during that time.”
Winde supplied the following information:
The ‘R’ number is currently 1.1 and the test positivity rate is 41.5%. New hospital admissions are at 339 per day, with a slight downturn. Deaths have increased, with about 108 deaths per day and will be the last indicator to fall.
Winde said that provincial authorities are simultaneously monitoring the number of trauma admissions to hospitals to ensure that there is sufficient capacity in the province’s hospitals and that it can proactively identify any risks so that they can be addressed. Senior CSIR researcher Ridhwaan Suliman, PhD, who was been analysing COVID data tweeted an update on Friday night, indicating that there was still no sign of the peak passing just yet:
Two new mutations in the toll-like receptor (TLR)7 gene have been discovered in healthy young men who experienced very severe COVID. This adds to the body of evidence suggesting that such mutations undermine a sufficient immune response against SARS-CoV-2, according to the study published in Frontiers in Immunology.
SARS-CoV-2 infection can lead to serious inflammation and even death, with risk factors including older age, male gender and chronic diseases such as diabetes and obesity. However these risk factors do not explain why (very) severe COVID also occurs in young, healthy men without a medical history.
Last year researchers reported that mutations in the TLR7 gene were a possible rare genetic risk factor. Two unrelated pairs of brothers became seriously ill with COVID and one of them died, according to the study. Both pairs of brothers had a mutation in the TLR7 gene, which encodes the receptor that plays a role in the recognition of the coronavirus and activates the antiviral immune response through interferon induction. TLR7 therefore seems to be important for immune defence against SARS-CoV-2.
Several subsequent studies had similar findings. An Italian study of men over 60 years of age with severe COVID found that more than 2 percent of severely affected men carried a genetic mutation in TLR7, giving rise to an impaired functioning TLR7 receptor, something not seen in the control group. The researchers again observed impaired activation of interferon signaling, showing that an optimal immune response could not be mounted. “A recently published study in the American Journal of Human Genetics, which looked for rare genetic risk factors through an association study in more than half a million people, also revealed TLR7 as the most important factor for severe COVID,” said geneticist Alexander Hoischen from Radboudumc Nijmegen, the Netherlands.
In the present study, the researchers, teaming up with Spanish scientists, screened 14 cases of severe COVID in young, healthy men under 50, of whom 10 were from Spain and four from the Netherlands. Hoischen said that “hitherto unknown mutations of the TLR7 gene were found in both a Spanish and a Dutch patient. In the Dutch patient again we saw the defective activation of the signaling and impaired production of interferon.”
The Dutch case was special because two of the patient’s cousins had the same mutation. Though not qualifying for vaccination at that time due to their young age, they were given priority based on the research. Study author Van der Made said that “as far as we know, these family members had not yet been exposed to the coronavirus. We therefore decided to vaccinate them preventively, in order to greatly reduce the risk of serious illness from COVID. In our small-scale study, we provide an impetus for screening a selected group of young men, precisely because a diagnosis of TLR7 deficiency due to mutations in this gene can have consequences for treatment, such as the mentioned preventive vaccination.” Hoischen further noted that: “Mutations in the TLR7 gene are now also listed as immune deficiency in OMIM – the international website where such information is registered.”
