Coronavirus Research Tracking - 9 September
hybrid immunity, new and improved vaccines, long Covid, BA.2.75, future pandemic prep
This week in vaccine research, a review of immune responses to vaccines, advantages of hybrid immunity, improving mRNA vaccines, and nasal vaccines in development.
In non-vaccine research, long Covid causes and treatments, cardiac-related problems after Covid, BA.2.75 variant is more immune susceptible than BA.4/5, differences in impacts between “zero Covid” and “living with Covid” strategies, why it took some time to accept SARS-CoV-2 was mainly transmitted through aerosols, aerosol transmission, and being better prepared for future pandemics.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Vaccine-related papers
Immune responses to vaccines
A review summarises current knowledge about immune responses to vaccines. Evidence shows that following an infection or vaccination neutralising antibodies are primarily responsible for blocking an infection while both antibody and CD8+ T-cell responses are involved in preventing severe Covid-19. CD8+ T-cells generated by vaccines provide cross reactivity to Omicron variants.
The paper recommends a greater focus on generating mucosal immunity to reduce infection risks, but notes the most important goal of vaccination is in preventing severe disease. Boosting every 4-to-6 months is not considered to be a desirable or practical long term strategy, due to “booster fatigue” and because it can neglect those (esp[ecially in less developed countries) who are not yet vaccinated. The paper was published in the New England Journal of Medicine.
Vaccines reduce transmission risks
A recent Nature news article reports on evidence of vaccines reducing the transmission risk of some Omicron sub-variants. It is largely based on a study of US prisoners (not yet peer reviewed). The study also showed that, unsurprisingly, transmission risk increases as time since vaccination increases.
Hybrid immunity generates novel nasal T cells.
CD8+ and CD4+ T cells found only in the nasal cavity were generated by infections after vaccination, but not by vaccination alone. These nasal T cells persisted for at least 3 months after infection. Absence of nasal T cells after just vaccination was surprising, and the reason(s) for it are not yet known.
The study only involved 50 vaccinated people, 34 of whom later became infected. Only a few markers were used to determine the tissue specificity of the T cells, so it is possible that the cells may also occur in non-nasal tissues. The paper was published in the Journal of Experimental Medicine.
Hybrid immunity reduces the rate of decline of neutralising antibodies
A small study found that there was a slower rate of decline in antibody neutralising activity after a third vaccine dose if the person also had had a breakthrough infection. The study involved 46 people who had received either the Pfizer or Moderna vaccine. Neutralisation activity was assessed up to nine months after the third dose. The paper was published in the New England Journal of Medicine.
An earlier Omicron infection improves protection in young children from a second infection
A previous Omicron infection or vaccination (two Pfizer doses) reduced the risk of another Omicron infection in children, at least for several months. A prior infection (with BA.1) plus vaccination provided greater protection against a BA.2 infection than a prior infection without vaccination (79% vs 63% at four months). The children were 5-to-11 years old, and over 800,000 were included in the study. The paper was published in the New England Journal of Medicine.
Improving mRNA vaccines
A news article in Science discusses how mRNA vaccines can be improved by changing their lipid delivery system. Current lipid nanoparticles can trigger adverse reactions and are also inefficient in releasing the mRNA when they enter cells. New lipid molecules and nanoparticles have been, and are being, developed.
Nasal vaccines
A news article in Nature discusses nasal spray (or mucosal) vaccines. It describes ones already in use for other diseases, and their degree of effectiveness. It also identifies current Covid-19 nasal vaccines in development or use, and points to the absence of large scale human trials so far, and challenges in assessing how effective they will be.
Non-vaccine-related papers
Covid-19 and children
A perspective published in Science notes that most Covid-19 research has been on adults. This article summarises what is known about severity and transmission in children, the prevalence of long Covid, why some children develop multi system inflammatory syndrome after an infection, and the benefits of vaccinating children.
Long Covid and autoreactive antibodies
Some long Covid cases have been linked to autoreactive antibodies. This study found that in some patients with severe Covid-19 antibody secreting cells that generate autoreactive antibodies do not disappear as the infection progresses. The study finds a correlation, rather than proving that auto-reactive antibodies are a cause of long Covid. The paper was published in Nature.
Causes of, and treatments for, long Covid
A news article published in the PNAS describes some potential causes of and treatments for long Covid. While some treatments, based on existing drugs, show promise, large clinical trials that assess their efficacy against long Covid are lacking. The article also notes the diversity of symptoms associated with long Covid, and the challenges associated with finding treatments that work well for individual patients.
Cardiac-related problems after Covid
A small study found that symptomatic Covid cases were more likely to have cardiac inflammations than asymptomatic cases three to four months after infection. The cardiac irregularities were relatively mild, but a year after their infection 57% of participants still had persistent cardiac symptoms. Difficulty breathing was the most common condition.
The study involved 346 participants with Covid-19 who had not been hospitalised, nor had existing cardiac problems. The authors emphasised that this was an exploratory study, with the techniques they used requiring further investigation. They stressed that the results can’t be extrapolated to estimate the incidence of cardiac problems in the general population after having Covid. The paper was published in Nature Medicine.
Loss of smell is not caused by infection of the olfactory bulbs
Research using hamsters found that loss of the sense of smell and infection of the olfactory bulbs are independent conditions with SARS-CoV-2 infection. Several variants were tested, and while all infected the olfactory bulb, some, such as Delta and Omicron, did not affect the sense of smell. Inflammatory effects that degrade the olfactory epithelium appear to be responsible for losing the sense of smell.
Small numbers of hamsters were used for each experiment. Further research is needed to confirm the same effects in people. The paper has not yet been peer reviewed.
Some antibodies can neutralise to some degree most variants
Nine antibodies isolated from people infected early in the pandemic demonstrated good neutralisation ability against most variants. These antibodies bind to the spike protein, but not at the site that binds to the ACE2 receptor. While their neutralisation ability is lower against the Wuhan strain than antibodies that bind to the ACE2 receptor site, their ability to bind to a broader range of variants of concern make them a potentially useful treatment.
Binding abilities were assessed using pseudoparticles rather than complete viruses. The paper was published in Communications Biology.
BA.2.75 does not avoid immune responses
A short article in The Lancet Infectious Diseases reports that the BA.2.75 sub-variant is less likely to avoid antibody neutralisation than the BA.4 and BA.5 sub-variants. It is slightly more resistant than the earlier BA.2 sub-variant. These results are consistent with other studies. Pseudoviruses were used to assess the neutralisation ability of sera from triple vaccinated healthcare workers and from 17 monoclonal antibodies.
Another study found that BA.2.75 is susceptible to three antiviral treatments and at least three monoclonal antibodies. Remdesivir, molnupiravir and Paxlovid were the antivirals. Three other monoclonal antibodies (individually or in combinations) did not show strong neutralising activity against BA.2.75. The paper was published in the New England Journal of Medicine.
Methods to detect SARS-CoV-2
A detailed review describes the different methods used to detect SARS-CoV-2, and the challenges still remaining. Some of the latter are the changing sensitivity of some methods at different stages of infection, the need to identify new epitopes on new variants, the high costs of PCR tests, and the need to use different methods or tests at different stages of the infection. The authors recommend development of portable biosensor-based detection systems. The paper was published in Trends in Analytical Chemistry.
Predicting future mutations of concern
A deep learning algorithm was used, in combination with in vitro testing, to predict what mutations in the receptor binding domain could affect infectivity and immune evasion. The algorithm accurately predicted (over 90%) binding to the ACE2 receptor, and antibody binding to the domain.
The model did not allow all sites in the receptor binding domain to change, and only sections of the protein were modelled at a time, not the whole protein, so predictions may not reflect real mutational and selection possibilities. The paper was published in Cell.
Excess deaths from “zero Covid” and “living with Covid” strategies
Within four countries “zero Covid” approaches resulted in lower excess mortalities compared to “living with Covid” strategies later in the pandemic. The countries included in the study were Singapore, South Korea, Australia, and New Zealand. Hong Kong, which kept a specialised zero Covid policy, was also included.
During “zero Covid” phases, percent excess mortality was under 10%, but this generally increased when “living with Covid” was adopted. New Zealand’s excess mortality during the “living with Covid” phase was lower than the other three countries (10% vs 30-40%). Despite Hong Kong retaining a zero Covid response, excess mortality was very high (54%) during its Omicron wave. The authors attribute Hong Kong's high mortality to low vaccination coverage.
Population density may in part explain the difference between NZ and the asian countries when restrictions were lower. Multigenerational living is also more common in Singapore, South Korea and Hong Kong, which contributes to higher transmission rates. The Omicron wave also occurred during winter in these countries, compared with summer/autumn in Australia & New Zealand. However, the authors did not suggest why Australian and New Zealand excess deaths were markedly different. The paper has not yet been peer reviewed.
A news article in Nature also discusses what has been learnt about lockdowns and other restrictions. Determining the benefits and costs of lockdowns is challenging. While lockdowns reduced transmission, the article notes the difficulty in determining by how much, and what other effects lockdown had because there were often no suitable counterfactuals. People’s behaviours often changed whether lockdowns occurred or not. Impacts of lockdowns also changed between infection waves. The article notes that lockdowns usually exacerbate inequalities
Factors that delayed accepting aerosol transmission of SARS-CoV-2
An article published in the BMJ highlights how, in the UK, cognitive biases, satisficing behaviours, mistaken beliefs, and other factors led to delays in recognising the virus spread largely by small aerosols rather than larger droplets. The UK government relied on too narrow a group of expert advisers. This in turn led to less effective public health measures and higher levels of infections and deaths in the UK early in the pandemic. The paper makes recommendations that the UK inquiry into the pandemic should consider.
The paper considers four hypotheses for a flawed narrative about transmission (psychological, scientific elitism, logistical, and political). It concludes that all probably contributed to the delay in adopting more effective transmission reduction measures.
Preparing for future pandemics
The CSIRO has published a report on how to prepare for future pandemics. It identifies six areas of science and technology in Australia that need to be supported, or improved, as well as six characteristics of the health system that need improving.