Coronavirus Research Tracking - 25 June
Delta variant, vaccine effectiveness, reinfections, variant mutations, long Covid, health system responses
Factors influencing the spread of the Delta variant in India have been published. The value of a single dose of vaccines for elderly people, and three doses for people with transplants. Good results for the Johnson & Johnson vaccine in an animal trial, while a new mRNA vaccine does badly, and encouraging results for pan-coronavirus vaccine development. Plus, risks of reinfections and long Covid, structural biology and mutations, and how to improve health system pandemic resilience.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Delta variant spread in India due to immune evasion and higher infectivity
In India the spread of the Delta variant has been attributed to a combination of evasion of neutralising antibodies and increased infectivity. This conclusion is based on lab tests showing the variant was less sensitive to neutralising antibodies from people infected with earlier strains, is able to replicate in cells quicker than the Alpha variant, and had about 8-fold reduced sensitivity to vaccine-elicited antibodies.
In vaccinated healthcare workers the Delta variant was the main variant found infecting these workers. These Delta variant “breakthrough cases” had higher viral loads, and showed greater rates of transmission between healthcare workers compared to other variants. The paper has not yet been peer reviewed.
First dose of vaccine shows benefits for the elderly
For people over 80, one dose of the BioNTech/Pfizer or AstraZeneca/Oxford vaccine can greatly reduce the risk of hospitalisation due to Covid-19. Over 400 hospital patients were involved in this study, with SARS-CoV-2 infections more common in unvaccinated patients than those who had previously received their first vaccine shot.
Vaccine effectiveness in relation to preventing severe disease after one dose was calculated to be around 80% for both vaccines during the same time period. The study was undertaken between December and February, before the spread of the Delta variant. The paper was published in The Lancet Infectious Diseases.
A larger study, involving 10,000 long-term care home residents, also found that single doses of these two vaccines reduced the risk of infection from four weeks onwards after vaccination. Vaccine effectiveness was 56% at 28–34 days and 62% at 35–48 days (though confidence intervals were broad). Lower viral levels were also found in vaccinated residents. The paper was also published in The Lancet Infectious Diseases.
Johnson & Johnson/Janssen vaccine works well against Beta variant (B.1.351) in macaques
The Johnson & Johnson/Janssen vaccine protects macaques from severe disease by the Beta variant. The vaccine generated strong antibody and T cell responses in the animals, although binding and neutralising antibody titers were 4-5-fold lower against the Beta variant, compared to a 2020 strain. Viral levels of the Beta variant were higher in vaccinated animals than the other strain, but vaccinated animals eliminated the Beta variant within four days after being infected. Lung damage in infected animals was minor compared to unvaccinated animals. Only a small number of animals were in each test group. The paper was published in Nature.
Poor performance by a new mRNA vaccine
Another mRNA vaccine, CVnCoV made by CureVac, was not very effective in Phase 3 trials. Efficacy was only 47%, compared to around 90% for Moderna’s and Pfizer/BioNTech’s vaccines. This seems, according to Derek Lowe, likely to be due to it not using modified nucleotides, which help prevent quick degradation of the RNA.
Three doses of vaccine help some immune-compromised people
Patients with kidney transplants have poorer immune responses to the Pfizer/BioNTech vaccine reports a paper published in Science Immunology.
Giving three doses of the Pfizer/BioNTech vaccine to people who had solid organ transplants significantly improved their production of antibodies. The patients received transplants several years ago, but remain immunocompromised.
Only 40 of 99 patients had antibodies after receiving the second dose, compared to 67 four weeks after having a third dose. There were no safety concerns associated with receiving three doses of teh vaccine. None of the patients who received three doses had become infected at the time the paper was published in the New England Journal of Medicine.
The results of these and other recent papers on transplant patients are summarised in a Science news article. It also discusses research indicating that two standard vaccine doses appear to work well for some cancer patients undergoing treatment.
Further evidence about feasibility for developing a pan-coronavirus vaccine
Manufactured messenger RNAs that have sequences from several coronavirus spike proteins appear to offer broad protection in mice. These so-called chimeric vaccines contained spike protein sequences with regions derived from up to three viruses, including a bat coronavirus, SARS, and different SARS-CoV-2 variants. The results indicate that a vaccine that provides protection against a broader range of coronaviruses is likely to be achievable. The paper was published in Science.
The role of interferon-I in vaccination side effects
Some of the side effects to vaccination (such as fever, headaches, and fatigue) are suggested to be due to a short spike in interferon production in response to the vaccine. The authors of this opinion, who note this is based on inference, emphasise that such reactions should be viewed positively as a sign that the vaccine is working. SARS-CoV-2 infection does not stimulate a large interferon-I reaction.
Not everyone reacts in the same way, and so absence of reactions does not mean the vaccine is not working. Females and younger people tend to have stronger vaccine reactions than males and older people, something that is seen in general immune responses. The article was published in Science Immunology.
Reinfection risks
Analyses by Public Health England found that there is a low risk of Covid-19 reinfection. Out of 4 million infections they report just under 16,000 possible reinfections (less than 0.4%). A possible reinfection was defined as two infections separated by at least 90 days, with negative tests in between. Fifty three reinfections were categorised as confirmed, being shown by genome sequencing to be genetically distinct.
Reinfection with SARS-CoV-2 appears to be more likely for people who are immunocompromised, have comorbidities, are obese or smoke. However, this is based on only a small number (23) of reinfection cases. The paper has not yet been peer reviewed.
Structural studies reveal how mutations affect interactions
Two papers show how changes in spike protein structure affects infectivity and immune evasion. In one paper, published in Science, the Beta variant (B.1.351) has changes to major neutralisation sites, making it more resistant to some antinbodies. While changes in the Alpha variant (B.1.1.7) structure increase binding affinity to the ACE2 receptor, probably accounting for its increased transmissibility.
The second paper, also in Science, reports similar results, and highlights that different sets of mutations have led to similar types of changes in the receptor binding domain. These have sometimes resulted in similar changes to transmissibility and immune evasion abilities. Knowledge of the structures of the spike protein variants helps anticipate further changes that may occur.
A mutation associated with higher pathogenicity
The P681R mutation in the B.1.617 lineage enhances viral fusion and promotes cell-cell infection. This may result in greater pathogenicity. However, the mutation does not appear to increase transmissibility. The experiments were performed using a pseudovirus, and the pseudovirus with this mutation was also found to be more resistant to neutralisation by sera from vaccinated people. The paper has not yet been peer reviewed.
Cases of Long Covid may be more common than previously thought
A Norwegian study reports that 61% of 312 infection cases still had symptoms six months after infection. This included many who had only had mild Covid-19 and were not hospitalised. Pre-existing lung disease (such as asthma) and high antibody titers were independently associated with persistent fatigue and total number of symptoms at six months.
Half of the young adults (16-30) in the study had persistent symptoms even though they had no comorbidities. Their long Covid symptoms included loss of taste and/or smell, fatigue, dyspnea, impaired concentration and/or memory problems. These may affect their ability to study and learn. The paper was published in Nature Medicine.
The UK React-2 study, involving half a million Covid-19 patients, found that one third (37%) reported at least one symptom persisting for more than 12 weeks. Women and older people more commonly reported persistent symptoms. A lower probability of long Covid was found in people of Asian ethnicities. Obesity, smoking or vaping, hospitalisation, and deprivation were associated with a higher probability of persistent symptoms. The paper has not yet been peer reviewed.
A letter in Nature Medicine highlights problems with some papers reporting long Covid. It notes the need for appropriate control groups to accurately identify persistent symptoms caused by Covid-19.
People may shed virus for longer than previously thought
Infected people may shed the virus for more than two weeks. A Canadian study, involving nearly 5,000 infected cases, found that the medium number of days the virus was shed was 19 days. The period of shedding varied for different groups. For infected residents in long-term care facilities they shed for three to five days longer, while infected people from higher income neighborhoods tended to have shorter periods of viral shedding. There are several possible explanations for these results, but no certainty which, if any, are more likely. The study did not assess the infectivity period. The paper was published in PLOS ONE.
Health system responses
An analysis of 28 countries’ health system responses to the pandemic identified four elements of health system resilience. These are:
activating comprehensive responses (such as active surveillance and whole-of-government responses to pandemics),
adapting health system capacity (such as supporting healthcare workers and creating temporary health facilities),
preserving health system functions (such as cost-effective procurement) and resources, and
reducing vulnerability (such as leveraging skills and knowledge from health workers and others to reach at-risk populations).
Six areas requiring urgent action were identified to build resilient health systems globally. The paper was published in Nature Medicine.
Understanding disease tolerance
A short Commentary in the Proceedings of the National Academy of Sciences suggests that the Covid-19 pandemic offers opportunities to better understand mechanisms of disease tolerance. This article referenced a paper from May in the same journal (covered in the 14 May Tracker) which found that 2% of infected people carried 90% of the virus in a group tested in Colorado, with asymptomatic and symptomatic patients showing similar ranges of viral loads. Other reports of supercarriers were reported in the 28 May Tracker.