Coronavirus Research Tracking - 13 May
Future vaccine prospects, three vaccine doses, Omicron lineages, long Covid
This week, how mRNA vaccines may be applied to other diseases, and how to improve longer lasting immunity for Covid-19. Also, three doses of several vaccines improve immune responses, and a doctor’s essay about having compassion toward the unvaccinated.
In other research, predicting new variants, key mutational sites in the virus, getting the timing right for Paxlovid, factors that may be associated with long Covid, antibodies that can neutralise many variants, and positive effects of breathing exercises.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Future mRNA vaccine prospects
A review in Nature Biotechnology considers the future prospects of mRNA vaccines and therapies. Current developments focus on infectious diseases and cancers, but other diseases and disorders are likely to be tackled soon.
Encouraging prospects for developing a vaccine that generates long-lasting immunity
A review of how other vaccines stimulate long-lasting immunity concludes that it is possible to develop a durable Covid vaccine. Factors that need to be considered for such a vaccine include the innate response that is initially triggered by the vaccine, the kinetics of antigen delivery and persistence, how well antigens stimulate initial B cells, and the memory B cells that respond to booster doses.
The article notes that the Johnson & Johnson/Janssen vaccine generates lower levels but longer lasting antibodies than the mRNA vaccines, so research into the effects of combining these two vaccine types in a vaccination programme would be useful. The paper was published in Immunity.
Three Pfizer doses improves viral neutralisation
A third dose of the Pfizer vaccine increased IgG levels 1.7-fold, and neutralisation activity 6.1-fold, compared with two doses. However, vaccine effectiveness against infection after three doses was 85.6%, relative to two (infections after three doses were low).
The study also found that individuals with lower antibody levels were less protected against infection than individuals with higher levels.
It involved 12,000 healthcare workers in Israel who had at least two vaccine doses. The paper was published in Nature Immunology.
Three doses of Sinopharm more effective against Omicron than two doses
Two doses of Sinopharm’s vaccine did not neutralise four Omicron sub-variants, but three doses enhanced neutralisation. The BA.1, BA.1.1, BA.2 and BA.3 sub-variants were tested. After three doses, neutralisation was five-to-six fold lower than for the wild-type virus.
Two vaccine doses followed by a Delta variant infection did not lead to significant neutralisation of the Omicron sub-variants.
The different sub-variants had different patterns of resistance to monoclonal antibodies. Thirteen of 20 monoclonal antibodies did not neutralise any of the sub-variants, but others were able to neutralise some but not all of them.
Sinopharm’s BBIBP-CorV is an inactivated whole virus vaccine. Sera from 10 double-vaccinated people, 20 triple BBIBP vaccinated, and 18 vaccinated with two BBIBP and one protein sub-unit vaccine dose were tested. Pseudoviruses were used to test neutralisation effectiveness. The paper was published in Cell Host & Microbe.
Similarities and differences in infections of BA.1 and BA.2
The BA.2 sub-variant does not infect cells more efficiently than BA.1, so another factor must increase transmissibility. Their immune evasion abilities differ though. BA.2 was not well neutralised by seven of eight antibodies used to treat Covid-19.
Both sub-variants (and BA.3) could be effectively neutralised by antibodies generated by three vaccine doses (Pfizer and/or AstraZeneca, with a third Pfizer dose). The paper was published in Cell Host & Microbe.
Compassion towards the unvaccinated
A letter in the Annals of Internal Medicine by a US doctor cautions that bias against unvaccinated people could create or contribute to systemic healthcare problems. The doctor’s personal account describes how, by listening more carefully to unvaccinated patients' reasoning, they went from anger toward them back to compassion as they understood the context that shaped people’s decisions.
Is predicting new variants becoming more feasible?
A news article in Nature discusses whether the emergence of new variants is becoming more predictable. The four most transmissible variants are all on the Omicron lineage, and variants after BA.1 appear to be increasing the ability to avoid the immune response.
However, other variants, such as Delta, are still around, and a quite different variant may still emerge. A new variant wave appears to develop about every six months. There is not enough information to predict when and from where another variant will emerge and spread widely.
Taking Paxlovid too early may lead to viral resurgence
A case study describes the return of Covid-19 symptoms about a week after a patient started taking Paxlovid. The male patient was 71 and had three vaccine doses. Paxlovid was given the day symptoms appeared every 12 hours for five days. Symptoms disappeared on the second day but returned 7 days later. The symptoms disappear for good three days after that.
The authors speculate that very early treatment may delay development of immunity, allowing viral loads to increase. The paper has not yet been peer reviewed.
Convergent evolution indicates limited number of immune escape possibilities
The mutations produced from a seven month infection in an immunocompromised person were usually not novel, indicating that a few specific mutations may provide a fitness advantage. Fifteen of 17 immune escape mutations had been found in other infections, suggesting considerable convergent evolution.
These mutation sites offer potential targets for new vaccines and therapies. The authors conclude that immunocompromised patients may pose a high risk of generating new variants of concern. The paper was published in Nature Communications.
Fewer people have long Covid symptoms after two years
A Chinese study found a significant decrease in people with long Covid symptoms between six months and two years after having Covid-19. At six months 68% had at least one symptom, but this fell to 55% when assessed at two years. Fatigue was the most common persistent symptom. Most (89%) were able to return to work by the second year.
However, participants who had had Covid-19 (with or without persistent symptoms) had poorer physical and mental health after two years than a control group who did not have Covid. Those who had severe Covid showed greater impairment two years later.
1,110 adults who had Covid-19 were assessed at six, 12 and 24 months. The study is ongoing. The paper was published in The Lancet Respiratory Medicine.
Some serum proteins linked to some long Covid cases
Some people with long Covid have distinct types of prolonged inflammation. Specific serum protein clusters and cellular signalling pathways are associated with these patients, so the pathways may be able to be used diagnostically.
Over 400 serum proteins were assessed. The study included 55 people with long Covid symptoms, as well as others without. The paper has not yet been peer reviewed.
Coronavirus “ghosts” could trigger long Covid
Fragments of the SARS-CoV-2 virus can remain in the digestive tract for months, potentially triggering long Covid. So far there is only evidence of a correlation not a causative effect, and more research is needed. Other studies have found viral fragments elsewhere in the body in people with (and without) long Covid symptoms. The research is summarised in a Nature news article.
Lower risk of long Covid from Omicron than Delta variant after two but not three vaccine doses
The risk of developing long Covid within two months of an Omicron BA.1 infection was about half that of a Delta infection. This was based on people who had two prior vaccine doses. For adults who were triple vaccinated there was no difference in long Covid risk between Delta and BA.1 or BA.2 variants (about 7-to-9% of infected cases) when assessed 4-to-8 weeks after the infection.
The odds of reporting Covid symptoms one to two months after infection were about 20% higher for BA.2 than BA.1 in triple vaccinated adults.
Results were adjusted to take account of socio-demographic differences. Participants had received the AstraZeneca or mRNA vaccines. Symptoms and vaccination status were self-reported. The report was published by the UK Office of National Statistics.
Antibodies that provide broad protection
A pan-variant antibody has been discovered. The S2X324 monoclonal antibody could effectively neutralise a range of variants, including BA.1, BA.2, BA.3, BA.4, BA.5 and BA.2.12.1. This antibody was also able to protect hamsters from Delta and BA.2 infections.
The study also showed, in line with other research, that three vaccine doses or hybrid immunity generate potent neutralising antibodies against BA.1 and BA.2 variants. An infection after vaccination induces neutralisation activity in nasal mucosas, a response not seen in people vaccinated but not infected.
Consistent with other studies, antibodies generated from an Omicron infection demonstrated very limited ability to neutralise other variants, unlike earlier variant infections. The paper has not yet been peer reviewed.
In another study, an antibody generated by the original SARS-CoV-2 strain can neutralise Alpha, Beta, Gamma, Delta, and BA.1 variants. Another was able to neutralise all but the BA.1 variant.
Structural analyses indicate that just two or three mutations in the spike protein can greatly diminish antibody binding. As has been seen for influenza, the authors suggest that reactivating some memory B cells, rather than generating new antibody types, is likely to provide more effective immune control. The paper was published in Science Immunology.
One aspect of adaptive immunity not affected by variant type
Variants of concern do not have a greater ability to suppress a key component of adaptive immunity than the original virus. The Major Histocompatibility I (MHC-I) complex helps activate CD8+ T-cells.
SARS-CoV-2, like some other viruses, can inhibit MHC-I. Despite variants of concern having different mutations in the ORF8 region, which is involved in inhibiting MHC-I, none of these mutations seem to affect the level of suppression. However, the mutations can have other impacts on immune responses. The paper has not yet been peer reviewed.
Estimating excess deaths requires good data sets
An analysis of excess deaths in Nordic countries disagrees with an earlier analysis (published in The Lancet, and featured in the 18 March Tracker) that concluded Denmark and Finland had unusually high mortality rates. The new analysis focuses on weaknesses and differences in methods to estimate excess mortality, rather than provide a new estimate.
Insufficient hard data, and inconsistencies in collection between areas, make the results from models unreliable the authors conclude. The paper has not yet been peer reviewed.
Breathing exercises can help aspects of persistent symptoms
A randomised controlled trial found that an online breathing and wellbeing programme can benefit people with persistent Covid symptoms. The programme improved mental health but not physical health. Some aspects of breathlessness were also improved. The method was based on singing.
The trial involved 150 participants, and the online programme ran for six weeks. The authors note that different types of breathing programmes will need to be developed to cater for people's preferences for different activities (such as singing, tai chi, and yoga). The paper was published in The Lancet Respiratory Medicine.
New diagnostic tests
New Zealand has started trialling a new type of diagnostic test - loop-mediated isothermal amplification (LAMP). [Some of these tests I can be called a reverse transcriptase LAMP test (RT-LAMP]. They usually provide greater accuracy than a rapid antigen test, but quicker results (in about 30 minutes) than a PCR test.
RT-LAMP tests have demonstrated high levels of sensitivity (85% or higher) and specificity (more than 90%) when compared with PCR results. There can be slight differences in accuracy between nasal swab and saliva samples, but the differences are generally small so that saliva testing may provide a less invasive but still accurate procedure. LAMP tests appear to be suitable for detecting infections in both symptomatic and asymptomatic adults. Recent test results have been published in the Journal of Molecular Diagnostics and in Scientific Reports.