I have been trying not to do yet another COVID-19 update, but I think there have been enough recent developments for a COVID-19 newsletter and sometimes it is worth repeating things.
New data
A large UK study (paper 1 below) in over 1.5 million COVID-19 cases confirms that cases of COVID-19 due to the Omicron variant are a lot milder than with Delta, which has now replaced Delta as the world’s dominant strain. In short, the evolution of Omicron has made it intrinsically a less severe virus.
After adjusting for past infection, vaccination status and so on, the study found that the risk of hospitalisation for Omicron cases was ~60% lower than for Delta. The risk of dying was ~70% lower. Importantly, unvaccinated people were also less sickened by Omicron than by Delta. Although vaccines were somewhat less effective against Omicron but still highly protective, in particular against severe disease. Three doses reduced the risk of hospitalisation or death by greater than 70%.
Some people are saying Omicron COVID-19 is now like the common cold. Yes, if you have some immunity and are healthy. No, if you have not been vaccinated and are vulnerable.
Please note there are two variants of Omicron the so-called BA1 and BA2 Omicron variants. The BA2 variant seems to be more infectious and is predicted to become the dominant strain as it displaces BA1. Inevitably, Omicron will be overtaken by other variants, which will continue to emerge. For example, some emerging variants combine the genetic changes seen in both Delta and Omicron and are being referred to as Deltacron and there are also strains emerging from South East Asia. The hope is that these strains will be weaker, which is what tends to happen as viruses become endemic.
Other news is that as both wildtype and vaccine immunity wanes additional boosters will help. This is has been shown in Israel and other studies and is why Moderna is applying to the FDA to get its license extended to cover a second booster. It is also clear that mixing vaccines is fine, i.e. if you have one specific vaccine in the past having a booster with a different vaccine works.
Please be aware that new vaccines to cover the newer strains are currently being studied and hence the COVID-19 vaccines will be a moving target. This is why it is almost a certainty vulnerable people will need annual or seasonal COVID-19 vaccines to help them cope with future strains. There is also work going on to develop a so-called universal coronavirus vaccine that targets antigens common to all strains of coronavirus. So only one vaccine will be required to cover SARS-CoV2, SARS-CoV-1, MERS, the common cold strains and potentially future emerging coronaviruses.
The good news is that people with MS who are vulnerable in particular those on anti-CD20 therapies begin to make antibody responses to booster doses of the vaccine. In the UK study below (paper 2) approximately one-third of pwMS who had failed to respond to the initial vaccine course developed anti-spike antibodies following a third COVID-19 vaccine. Two-thirds of participants had T cell response to vaccination. Although no people taking fingolimod mounted a T cell response to vaccination, I think this is a methodological problem with too few circulating T-cells for the assays to work. It is important to note that pwMS on S1P modulators handle COVID-19 very well with no increased risk of severe disease compared to pwMS on other DMTs that are not immunosuppressive. This would imply their immunity is fine. So if you are on fingolimod or another S1P modulator keep calm and carry on. I would not advise you to stop or interrupt the dosing of your medication.
Another bit of good news is the MHRA licensed AstraZeneca’s antibody combination of tixagevimab co-packaged with cilgavimab (Evusheld) for use as pre-exposure prophylaxis (prevention) for COVID-19. This antibody covers Omnicron and other variants. It remains to be seen how the NHS will use Evusheld, but it may be used in the most vulnerable patients, for example, pwMS undergoing AHSCT or about to receive alemtuzumab.
Another group of patients who may benefit from Evusheld are vulnerable pregnant mothers. Please note that in general antibody therapies targeting SARS-CoV-2 should be safe in pregnancy. Even if the antibodies cross the placenta during the second and third trimester of pregnancy they are unlikely to cause problems for the unborn baby as they are not targeting self-antigens. In fact, the antibodies crossing the placenta will provide passive anti-SARS-CoV-2 immunity to the baby. In comparison, a therapeutic antibody such as an anti-CD20 antibody will cross the placenta and deplete the baby’s B-cells.
Other important developments include the ongoing testing of anti-inflammatory treatments for patients with severe COVID-19. Recently baricitinib (Janus kinase 1/2 inhibitor) an oral anti-inflammatory therapy to treat rheumatoid arthritis and atopic dermatitis was shown to improve the outcome of patients with severe COVID-19.
Many pwMS are emailing me for advice alarmed at the rising number of cases of COVID-19 in the UK. This is almost certainly driven by (1) falling immunity, (2) emerging new variants (BA2, etc.) and (3) relaxing of social distancing and other personal hygiene measures. I am getting daily reports from patients and colleagues coming down with COVID-19. They are all complaining of a cold and in the last few weeks, none of the pwMS reporting they have COVID-19 have needed hospitalisation. So I think we are really moving into the tail of the pandemic and the messages remain the same.
Get vaccinated and/or boosted according to the guidelines regardless of what DMT you are on.
If you are on ocrelizumab you may want to wait until you are 3+ months since your last infusion before being vaccinated or boosted.
Get yourself on the vulnerable list so that you have access to rapid PCR testing and if positive you will get antiviral therapies in the community
Start getting back to normal, i.e. socialising and meeting family and friends.
Remain cautious about high-risk behaviours, but if you are going to get COVID-19, which is likely to happen to all of us at some point, now is probably the best time to get it. That is when you have some background immunity, a relatively benign circulating strain, antiviral therapies to protect the most vulnerable, new treatments for severe COVID-19 and an NHS that has surge capacity.
The Endgame
When I was a child, my mother and her friends used to have chicken pox parties to make sure their children got chickenpox when they were still toddlers so that they would not be at risk as older children of getting the more severe late-onset disease. Society had worked out how to use wild-type mild early infection to protect their children from more severe late infection. I suspect this is what the Government in the UK is doing right now. The Government is hoping as many people get mild wild-type COVID-19 infection to drive up herd immunity. This change in philosophy is telling us that public health officials are currently playing the endgame of the COVID-19 pandemic. This in itself must be good news and even more so as Spring has arrived.
Paper 1
Background: The omicron variant (B.1.1.529) of SARS-CoV-2 has demonstrated partial vaccine escape and high transmissibility, with early studies indicating lower severity of infection than that of the delta variant (B.1.617.2). We aimed to better characterise omicron severity relative to delta by assessing the relative risk of hospital attendance, hospital admission, or death in a large national cohort.
Methods: Individual-level data on laboratory-confirmed COVID-19 cases resident in England between Nov 29, 2021, and Jan 9, 2022, were linked to routine datasets on vaccination status, hospital attendance and admission, and mortality. The relative risk of hospital attendance or admission within 14 days, or death within 28 days after confirmed infection, was estimated using proportional hazards regression. Analyses were stratified by test date, 10-year age band, ethnicity, residential region, and vaccination status, and were further adjusted for sex, index of multiple deprivation decile, evidence of a previous infection, and year of age within each age band. A secondary analysis estimated variant-specific and vaccine-specific vaccine effectiveness and the intrinsic relative severity of omicron infection compared with delta (ie, the relative risk in unvaccinated cases).
Findings: The adjusted hazard ratio (HR) of hospital attendance (not necessarily resulting in admission) with omicron compared with delta was 0·56 (95% CI 0·54–0·58); for hospital admission and death, HR estimates were 0·41 (0·39–0·43) and 0·31 (0·26–0·37), respectively. Omicron versus delta HR estimates varied with age for all endpoints examined. The adjusted HR for hospital admission was 1·10 (0·85–1·42) in those younger than 10 years, decreasing to 0·25 (0·21–0·30) in 60–69-year-olds, and then increasing to 0·47 (0·40–0·56) in those aged at least 80 years. For both variants, past infection gave some protection against death both in vaccinated (HR 0·47 [0·32–0·68]) and unvaccinated (0·18 [0·06–0·57]) cases. In vaccinated cases, past infection offered no additional protection against hospital admission beyond that provided by vaccination (HR 0·96 [0·88–1·04]); however, for unvaccinated cases, past infection gave moderate protection (HR 0·55 [0·48–0·63]). Omicron versus delta HR estimates were lower for hospital admission (0·30 [0·28–0·32]) in unvaccinated cases than the corresponding HR estimated for all cases in the primary analysis. Booster vaccination with an mRNA vaccine was highly protective against hospitalisation and death in omicron cases (HR for hospital admission 8–11 weeks post-booster vs unvaccinated: 0·22 [0·20–0·24]), with the protection afforded after a booster not being affected by the vaccine used for doses 1 and 2.
Interpretation: The risk of severe outcomes following SARS-CoV-2 infection is substantially lower for omicron than for delta, with higher reductions for more severe endpoints and significant variation with age. Underlying the observed risks is a larger reduction in intrinsic severity (in unvaccinated individuals) counterbalanced by a reduction in vaccine effectiveness. Documented previous SARS-CoV-2 infection offered some protection against hospitalisation and high protection against death in unvaccinated individuals, but only offered additional protection in vaccinated individuals for the death endpoint. Booster vaccination with mRNA vaccines maintains over 70% protection against hospitalisation and death in breakthrough confirmed omicron infections.
Paper 2
Background: Uncertainties remain about the benefit of a 3rd COVID-19 vaccine for people with attenuated response to earlier vaccines. This is of particular relevance for people with multiple sclerosis (pwMS) treated with anti-CD20 therapies and fingolimod, who have substantially reduced antibody responses to initial vaccine course.
Methods: PwMS taking part in a seroprevalence study without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/-venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. The relationship between evidence of prior COVID-19 infection and immune response to COVID-19 vaccine 3 was evaluated using Fishers exact test.
Results: Of 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There no association between laboratory evidence of prior COVID-19 infection and anti-spike seroconversion following COVID-19 vaccine 3.
Conclusions: Approximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine.
What is already known: The benefits of COVID vaccination are well described. It is unknown whether there is additional benefit afforded from a third COVID-19 vaccination in those people who have failed to mount a serological response to their initial vaccine course.
What this study adds: Approximately one third of people with MS in our study, all of whom had failed to response to initial vaccine course, developed anti-spike antibodies following a third COVID-19 vaccine. Two-thirds of participants had T cell response to vaccination. No people taking fingolimod appeared to mount a T cell response to vaccination.
How this study might influence practice: These findings highlight potential benefits of booster vaccinations to a substantial proportion of immunosuppressed people who have failed to respond to initial vaccination course. The clinical correlates of antibody and T-cell responses to COVID-19 remain uncertain but they are almost certainly associated with milder subsequent disease in the general population.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
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