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Vaccination found to reduce risk of post-COVID-19 condition

5th January 2023

Vaccination against COVID-19 appears to provide a small but significant protection against the development of post-COVID-19 condition

Receiving a COVID-19 vaccination has been found to reduce the risk of subsequently developing post-COVID-19 condition (or long covid) although the vaccine effectiveness is low according to the findings of a meta-analysis by US researchers.

Vaccine effectiveness is a measure of how well vaccination protects individuals against a condition but differs from the efficacy measured in a trial, because efficacy cannot predict exactly just how effective a vaccine might be in a larger and more variable population. Nevertheless, real-world evidence suggests that some vaccines, such as BNT162b2, have an effectiveness comparable to that reported in phase III clinical trials. Although in practice, many patients make a full recovery after an acute COVID-19 infection, for a minority, there is the continuation or development of other symptoms. The World Health Organisation has described this as ‘Post COVID-19 condition’ and which occurs in individuals with a history of probable or confirmed COVID-19 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.

While the effectiveness of vaccination against COVID-19 is widely accepted, what is uncertain, is whether vaccination reduces the risk of post–COVID-19 condition. This was the subject of the current study by the US researchers who reviewed the literature on the effectiveness of COVID-19 vaccines for post–COVID-19 condition and pooled the results of published studies to allow for a more precise estimate of effectiveness. The team looked for studies that: involved vaccinated and unvaccinated individuals and evaluated the long-term effectiveness of the COVID-19 vaccine. Post–COVID-19 conditions were defined as a wide range of health symptoms that were present 3 or more weeks after having COVID-19. Any studies without a comparison between vaccinated and unvaccinated individuals (or other vaccinated control group) were excluded. The team calculated the pooled diagnostic odds ratio (DORs) for post–COVID-19 conditions between vaccinated (i.e., those who received at least 1 dose of a COVID-19 vaccine) and unvaccinated individuals.

Vaccination and effectiveness against post-COVID-19 condition

A total of 10 studies with 1,600,830 individuals evaluated the effect of vaccination on post–COVID-19 conditions and of which 6, were included in the meta-analysis. The pooled prevalence of post–COVID-19 conditions was 39.1% among those who were unvaccinated and 37.6% among those who received at least 1 dose.

The pooled DOR for post–COVID-19 conditions among individuals who received at least 1 dose was 0.708 (95% CI 0.69 – 0.73), giving an estimated vaccine effectiveness of 29.2% (95% CI, 27.5%–30.8%).

However, vaccine effectiveness varied depending on whether an individual received the vaccine before or after being infected with COVID-19. For example, effectiveness was 35.3% (95% CI 32.3% – 38.1%) among those who received the COVID-19 vaccine before having COVID-19 but 27.4% (95% CI 25.4% – 29.3%) among those who received it after being infected.

The authors concluded that COVID-19 vaccination before and after having COVID-19 provided a low but statistically significant decrease in post–COVID-19 conditions for the variants circulating during the study period. They added that a more standardised definition of post–COVID-19 conditions was also needed both for research and clinical purposes.

Marra AR et al. The effectiveness of coronavirus disease 2019 (COVID-19) vaccine in the prevention of post–COVID-19 conditions: A systematic literature review and meta-analysis. Antimicrob Steward Health Epidemiol 2022

Antibody response from Omicron BA.4/BA.5 bivalent booster similar to original vaccine

31st October 2022

The antibody response to an Omicron BA.4/BA.5 bivalent booster appears to be similar to that generated after a fourth monovalent mRNA vaccine

The antibody response generated after receipt of an Omicron BA.4/BA.5 bivalent booster appears no better than the response induced after a fourth dose of monovalent mRNA vaccine dose against COVID-19 variants according to a small pre-print study by a team of US researchers.

The evolving nature of the COVID-19 virus had led to many variants such as Omicron. However, this variant too has further mutated to create the sublineages BA.2.12.1, BA.4 and BA.5 that which can escape neutralisation by current vaccines. As a result, companies have quickly adapted their vaccines and the FDA has given emergency use authorisation to what have been termed ‘bivalent boosters’ produced by both Moderna and Pfizer-BioNTech. Similarly, the European Medicines Agency, has also recommended authorising an adapted bivalent vaccine targeting the Omicron sub-variants BA.4 and BA.5.  The bivalent vaccines contain two messenger RNA components of COVID-19; one directed at the original strain and the other towards the BA.4 and BA.5 lineages of the omicron variant. There is currently limited data on the antibody response generated with these bivalent vaccines. However, one recent study compared the Moderna bivalent vaccine as a second booster to receiving a fourth dose of the original, monovalent vaccine. The results showed that the bivalent vaccine elicited a higher neutralising antibody response against omicron BA.4 and BA.5 than the monovalent vaccine. Moreover, preliminary data on a bivalent vaccine manufactured by Pfizer BioNTech, was reported to show that in sera collected from participants 7 days after administration of a 30-µg booster dose of the Omicron BA.4/BA.5-adapted bivalent COVID-19 vaccine, there was a substantial increase in the Omicron BA.4/BA.5 neutralising antibody response above pre-booster levels.

In the present study, researchers collected sera from individuals who had previously received three doses of a monovalent vaccine, followed by a single dose of a bivalent vaccine. The researchers then compared the neutralising capacity against COVID-19 to panels of sera collected from participants who had received either 3 or 4 monovalent mRNA vaccine doses as well as from individuals who experienced a breakthrough infection with BA.4/BA.5. The sera samples were all tested against the original COVID-19 strain, Omicron sublineages, BA.1, BA.2, BA.4/BA.5, BA.4.6, BA.2.75 and BA.2.75.2.

Antibody response for COVID-19 variants

A total of 74 patients provided samples of whom, 19 with a mean age of 55.3 years (89.5% female) had previously received four doses of a monovalent vaccine although those who were given a bivalent booster were younger (mean age 36.4, 76.2% female). Serum samples were collected a mean of 24 days following the booster dose for the monovalent group and after a similar interval (mean 26.4 days) in the bivalent group.

All the cohorts displayed a high antibody response to the original COVID-19 strain but there were no differences for the other variants. In other words, receiving a booster vaccine which targeted both the original COVID-19 strain and the BA.4/BA.5 variants, did not produce a superior antibody response against all of the variants tested, compared to boosting with a fourth dose of a monovalent vaccine.

The authors suggested that these results may indicate immunological imprinting, i.e., whereby initial exposure to one virus strain effectively primes B cell memory and limits the development of memory B cells and neutralising antibodies against new minor variant strains of the virus. Moreover, they suggested that follow-up studies were needed to determine if the antibody responses change over time.

Wang Q et al. Antibody responses to Omicron BA.4/BA.5 bivalent mRNA vaccine booster shot. BioRxiv 2022

Triple dose COVID-19 vaccination significantly reduces risk of long covid

29th August 2022

Triple dose COVID-19 vaccination is significantly associated with a reduced risk of developing long covid among non-hospitalised patients

A triple dose vaccination against COVID-19 is associated with a significantly reduced risk of developing long covid among individuals who experience a breakthrough infection but who do not require hospitalisation according to the results of a study by a team of Italian researchers based in Milan.

Following an acute infection with COVID-19, it has become widely recognised that some patients can develop post-acute sequelae, i.e., long covid, 6 months after their initial infection. Potential risk factors linked to the development of long covid include female gender, respiratory symptoms at the onset and the severity of the initial illness. With the widespread introduction of vaccination against COVID-19, there remains some uncertainty over whether vaccination and in particular, triple dose vaccination, protects against the development of long covid. To date, only one study has examined the relationship between vaccination, breakthrough infections and long covid. In that study, the authors suggested that among individuals who experience a breakthrough infection, there was a 15% lower risk of post-acute sequelae. However, a limitation of the study was that the authors only considered the risk reduction after two doses of a COVID-19 vaccine, whereas current recommendations are for individuals to receive a triple dose.

For the present study, the Italian team set out to examine the impact of a triple dose vaccination on the development of long covid. They turned to healthcare professionals who had received three doses of the BNT162b2 vaccine and did not require hospitalisation if they developed a breakthrough infection. The researchers also defined long covid as the presence of at least one COVID-19 related symptom which continued for more than 4 weeks. They also considered the three COVID-19 waves and used multi-variable logistic regression to assess the relationship between the development of long covid and patient demographics, co-morbidities and vaccination status.

Triple dose vaccination and long covid

A total of 739 individuals with a mean age of 42.8 years (25.4% male) were included, of whom, 31% developed long covid and 16% of these individuals had received a triple dose of BNT162b.

The incidence of long covid varied depending on the pandemic wave. During the first wave (February – September 2020), 48.1% were affected, reducing to 35.9% in wave 2 (October 2020 – July 2021) and 16.5% in wave 3 (August 2021 – March 2022).

The number of vaccine doses was also associated with the development of long covid which ranged from 41.8% among unvaccinated individuals, to 30% in those with a single dose, 17.4% after two doses and 16% in those after a triple dose of vaccine.

Using unvaccinated women in wave 1 without allergies or co-morbidities as the reference point, having 2 vaccine doses significantly reduced the risk of long covid (odds ratio, OR = 0.25, 95% CI 0.07 – 0.87, p = 0.03) but this was reduced further still among those with three doses of the vaccine (OR = 0.16, 95% CI 0.03 -0.84, p = 0.03).

The authors concluded that among those receiving a triple dose vaccination against COVID-19, who develop a breakthrough infection which does not lead to hospitalisation, there was a significantly lower risk of developing long covid.

Azzolini E et al. Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers JAMA 2022

Hypertension remains a significant risk factor for severe COVID-19 in fully vaccinated

17th August 2022

The presence of hypertension still poses a significant risk factor for more severe disease in COVID-19, even among those fully vaccinated

Patients with hypertension even after receipt of three COVID-19 vaccination doses, remain at an elevated risk of severe breakthrough infections with the Omicron variant according to researchers from the Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, US.

Although full vaccination against COVID-19 initially required individuals to have two doses, the fact that immunity appears to wane over time has led to a recommendation for a third dose. In fact, a third dose appears to provide greater protection with data showing how a third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against COVID-19 compared with two doses. As more information emerged during the pandemic, it became clear that there were several important risk factors associated with the development of more severe illness and hypertensive patients were found to be more vulnerable to the development of serious complications. However, several unanswered questions remained. For example, do the same risk factors apply with COVID-19 variants and does full vaccination mitigate these risk factors? These were the questions raised in the present, retrospective analysis by the US team.

The researchers examined a cohort of adults with at least three doses of the COVID-19 vaccine but who subsequently developed a breakthrough infection with the Omicron variant (confirmed by nasopharyngeal swabs and PCR testing) and were hospitalised at their centre. The team collected demographic and co-morbidity data and used multivariable logistic regression analysis to assess the association between various factors such as age, comorbid conditions and the risk of hospitalisation and these covariates were adjusted for in the final analysis.

Hypertension and risk of severe illness

The researchers identified a total of 912 patients with a mean age of 56 years (41% male) of whom 15.9% were subsequently hospitalised with a breakthrough Omicron infection. Among the overall cohort, 27% were obese, 21% had diabetes and 54% were hypertensive and there was a mean of 72 days between vaccination and infection.

In regression analysis, the presence of hypertension was associated with a more than two-fold higher odds of being hospitalised, after adjustment for covariates (odds ratio, OR = 2.29, 95% CI 1.24 – 4.32). Other related elevated risk factors included the presence of a previous myocardial infarction (OR = 2.21, 95% CI 1.29 – 3.77).

Because hypertension is common in patients with a prior myocardial infarction, heart failure and chronic kidney disease, in a further analysis, the authors excluded patients with these three comorbidities. However, the elevated risk of hospitalisation in those with hypertension remained significant (OR = 2.54, 95% CI 1.32 – 5.37).

The authors concluded that the presence of hypertension remains an important risk factor for breakthrough COVID-19 infections even after full vaccination and that further research is required to understand the relationship between this risk factor to enable the development of mitigation strategies.

Ebinger J et al. Hypertension and Excess Risk for Severe COVID-19 Illness Despite Booster Vaccination Hypertension 2022

COVID-19 vaccination reduces infection-related myocardial infarction and stroke risk

9th August 2022

COVID-19 vaccination significantly reduces the risk of both an acute myocardial infarction and stroke among those infected with the virus

COVID-19 vaccination provides individuals with a reduced risk of experiencing an acute myocardial infarction or ischaemic stroke after becoming infected with the virus according to the findings of a study by Korean researchers.

It has now become recognised that following an acute infection with COVID-19, beyond the first 30 days, individuals with COVID-19 have an increased risk of cardiovascular disease and which includes cerebrovascular disorders, dysrhythmias, ischaemic and non-ischaemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. While it is clear that a COVID-19 vaccination is safe and offers protection against severe COVID-19, hospitalisation and death against all current variants of concern, what is less clear is whether vaccination is able to reduce the post-infection cardiovascular sequelae. As a result, for the present study, the Korean researchers undertook a retrospective cohort study and compared the incidence of acute myocardial infarction and ischaemic stroke in those with and without full COVID-19 vaccination. They linked data from the Korean nationwide COVID-19 registry and the National Health Insurance database and included all adults who were diagnosed with COVID-19 between July 2020 and December 2021. However, the team excluded several patient groups including: individuals whose data showed that they had a cardiovascular event three months before a COVID-19 infection, cases of re-infection with the virus and patients who were vaccinated but hospitalised with the virus for longer than 30 days. They set the primary outcome of interest as a composite of all hospitalisations for an acute myocardial infarction and ischaemic stroke and which had occurred 31 to 120 days after an individual’s COVID-19 diagnosis. They decided to exclude cardiovascular events within the first 30 days of infection because of the inherent difficulty of differentiating whether the event was related to infection of treatment.

COVID-19 vaccination and cardiovascular outcomes

A total of 231,037 patients were included in the analysis, of whom, 62,727 were unvaccinated and with a median age of 42 years (51.5% female). The median age of the vaccinated group was higher (57 years) and had a greater incidence of co-morbidities including diabetes (11.8% vs 7.1%, vaccinated vs unvaccinated) and hypertension (22.1% vs 10.8%). Furthermore, a higher proportion of unvaccinated individuals had severe COVID-19 (3.1% vs 9.8%). The median period of follow-up was 90 days in the unvaccinated and 84 days in the fully vaccinated group (which was defined as receipt of 2 doses of a vaccine).

The composite outcome occurred in 31 unvaccinated individuals and 74 of those who were fully vaccinated and after adjustment for differences in baseline characteristics, this difference was statistically significant (hazard ratio, HR = 0.42, 95% CI -.29 – 0.62, p < 0.001). This difference was also significant for the individual components of the composite.

The authors concluded that full COVID-19 vaccination was protective against the acute myocardial infarction and an ischaemic stroke that could arise after infection with the virus, compared with individuals who were unvaccinated.

Kim YE et al. Association Between Vaccination and Acute Myocardial Infarction and Ischemic Stroke After COVID-19 Infection JAMA 2022

Vaccination protects overweight and obese against severe COVID-19 and death

12th July 2022

Overweight and obese patients protection against severe disease and death when infected with COVID-19 is similar to those of a healthy weight

Both overweight and obese patients who have been vaccinated against COVID-19 have a similar degree of protection against severe disease and death as those of a healthy weight according to a large, population-based cohort study by researchers from the UK and Spain.

Since the start of the COVID-19 pandemic, considerable evidence has emerged indicating how obesity is a risk factor for more severe disease. For example, in a 2020 systematic review of 24 retrospective cohort studies, the odds ratio for intensive care unit admission for obese patients was 1.21 and higher still, for invasive mechanical ventilation (OR = 2.05). With the widespread introduction of COVID-19 vaccines, it is necessary to understand how overweight and obese patients respond to vaccination. This is especially important in light of evidence showing that despite generating a robust serological response, vaccinated obese adults are twice as likely to develop influenza and influenza-like illness compared with healthy weight adults. Furthermore, another study found that CD4(+) and CD8(+) T cells from overweight and obese individuals expressed lower levels of CD69, CD28, CD40 ligand, and interleukin-12 receptor, compared with healthy weight and which may contribute to the increased morbidity and mortality from H1N1 influenza A virus.

Despite the concern that overweight and obese patients may not produce a satisfactory immune response to vaccination, there are limited data on the association between body mass index (BMI) and COVID-19 vaccine effectiveness and the risk of severe COVID-19 outcomes after vaccination. Using the QResearch database, in the present study, researchers used an anonymised patient data set derived from over 1,700 general practices in England and collated demographic and clinical data. They linked this information with the NHS Digital database of positive COVID-19 tests, hospital episode statistics and death certificates. Included patients were adults and who had a BMI measurement recorded in their medical records and which were then categorised as underweight (BMI < 18.5), healthy weight (BMI 18.5 – 24.9), overweight (BMI 25 – 29.9) and obese (BMI > 30). They examined vaccine effectiveness across the different weight categories and set the main outcomes of interest as hospitalisation and death.

Overweight and obese patients and severe COVID-19 outcomes

A total of 9,171,524 individuals with a mean age of 52 years (47% male) were included in the analysis. During the period of study there were 566,461 positive tests for COVID-19, 32,808 COVID-19-related hospital admissions and 14,389 COVID-related deaths. Across the whole cohort, 19.2% were unvaccinated, 3.1% had at least one dose, 52.6% two doses and 25% three doses. Uptake of two or three vaccine doses was more than 80% among those deemed overweight or obese.

At least 14 days after the second vaccine dose, the likelihood (based on the odds ratio, OR) of a COVID-19-related hospitalisation (compared to those who were unvaccinated) was lowest for those who were either overweight (OR = 0.32, 95% CI 0.30 – 0.34) or obese (OR = 0.32, 95% CI 0.30 – 0.34) which was similar to those with a healthy weight (OR = 0.34). Among those who were underweight, there was a slightly higher risk of hospitalisation (OR = 0.51, 95% CI 0.41 – 0.63). However, the odds of hospitalisation after a third vaccine dose were significantly less and similar for each of the different BMI categories.

In relation to mortality, there was a similar pattern 14 days after the second dose, e.g., underweight individuals (OR = 0.60), healthy weight (OR = 0.30) with overweight and obese individuals having the same odds ratio (OR = 0.26). Mortality was also significantly lower after the third dose though there was more uncertainty given the lower number of cases.

The authors concluded that both overweight and obese patients appear to be equally well protected against severe COVID-19 outcomes as those of a healthy weight although vaccine effectiveness appeared to be less in those classed as underweight.

Piernas C et al. Associations of BMI with COVID-19 vaccine uptake, vaccine effectiveness, and risk of severe COVID-19 outcomes after vaccination in England: a population-based cohort study Lancet Diabetes Endocrinol 2022

Paxlovid remains effective in those vaccinated against COVID-19

4th July 2022

Israeli researchers have found that paxlovid use in those at risk of COVID-19 progression remains effective even in fully vaccinated patients

The effectiveness of the anti-viral drug paxlovid in preventing the progression of COVID-19 remains even in those who have been adequately vaccinated against the virus according to the results of a real-world study by Israeli researchers.

Paxlovid consists of nirmatrelivir, a protease inhibitor against COVID-19 and ritonavir, which reduces the in vivo metabolism of nirmatrelivir. The published data for the drug (the EPIC-HR trial) suggested that treatment of symptomatic COVID-19 in patients at risk of progression to severe disease, results in an 89% lower risk compared to placebo. Nevertheless, the study was undertaken before omicron became the main circulating variant and therefore the generalisability of the study’s findings are potentially limited. Consequently, for the present study, the Israeli team decided to undertake a large, retrospective cohort study of high-risk COVID-19 patients, to assess the effectiveness of paxlovid at preventing progression to severe COVID-19 and subsequent death during the time when omicron was the predominant strain.

Using a large, national health service database, the researchers identified all adults (18 years and over) who tested positive for COVID-19 but restricted the search to those who would be suitable candidates for treatment with paxlovid, i.e., those who were older than 60 years, with a body mass index (BMI) greater than 30 and with co-morbidities including diabetes, hypertension and cardiovascular disease. However, unlike in the EPIC-HR trial, where those who had been vaccinated were excluded, for the present analysis, researchers included patients, regardless of their vaccination status. The main outcome of the study was a composite of severe COVID-19 or COVID-19-related mortality. For their analysis, the researchers included demographic and co-morbidity data and which were adjusted for in the analysis.

Paxlovid and progression of COVID-19

A total of 4,737 individuals with a mean age of 68.5 years (42.1% male) were treated with paxlovid and compared with 175,614 individuals who tested positive but who did not receive the drug. In total, 77.8% of those given paxlovid had adequate COVID-19 vaccination compared to 75% of those in the non-paxlovid group.

Overall, the primary outcome occurred in 39 individuals receiving paxlovid compared to 903 in those not given the drug. Paxlovid was therefore associated with a significantly lower risk of severe COVID-19 or mortality (hazard ratio, HR = 0.54, 95% CI 0.39 – 0.75). Moreover, among the whole cohort, having adequate COVID-19 vaccination, was also associated with a significantly lower risk of the primary outcome (HR = 0.20, 95% CI 0.17 – 0.22).

When the analysis was restricted to those diagnosed with COVID-19 when omicron was the main circulating variant, paxlovid was also associated with a greater reduction in the primary endpoint (HR = 0.43, 95% CI 0.64 – 0.85). Interestingly, among those given paxlovid and who were adequately vaccinated, there was still a significant reduction in the primary outcome (HR = 0.62, 95% CI 0.39 – 0.98) as well as among those not vaccinated (HR = 0.52, 95% CI 0.32 – 0.82).

The authors concluded that their study had demonstrated that in a real-world setting and during the period of time when omicron was the dominant variant, paxlovid was associated with a significant reduction in progression of COVID-19 and COVID-19-related mortality.

Najjar-Debbiny R et al. Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients Clin Infect Dis 2022

Stopping methotrexate for 2 weeks after COVID-19 vaccination boosts immune response

30th June 2022

Halting methotrexate for two weeks after a COVID-19 vaccination boosted the level of antibodies generated compared with continued drug use

Stopping methotrexate (MTX) for two weeks after a third COVID-19 vaccination significantly enhanced the level of antibodies produced compared to continuing with the drug, according to the results of a randomised trial by a team of UK researchers.

The use of the immunomodulatory drug methotrexate, is known to adversely affect the humoral and cellular immune response to COVID-19 mRNA vaccines. In fact, studies have shown that seroconversion rates after COVID-19 vaccination are significantly lower in immunocompromised patients, especially organ transplant recipients. As a result, it is important to implement strategies that can enable those who are immunocompromised to mount a satisfactory immune response. It has been shown that discontinuation of immunosuppressant drugs such as methotrexate in patients with rheumatoid arthritis, for either 4 weeks before, 2 weeks before and for 2 weeks after vaccination, improves the immunogenicity of seasonal influenza vaccination. In fact, the highest immune response occurred when MTX was discontinued two weeks after vaccination and this effect was confirmed in another study that specifically focused on stopping the drug two weeks after seasonal influenza vaccination.

Since the effectiveness of this approach has not been formally evaluated for the COVID-19 vaccine, for the present study, the UK undertook a randomised trial among immunocompromised patients prescribed methotrexate. The Vaccine Response On/Off Methotrexate (VROOM) trial, randomised participants 1:1 to either suspension of MTX (suspend methotrexate) for two weeks immediately after their COVID-19 booster dose, or to continue with the drug as usual (continue methotrexate). Individuals were recruited from both rheumatology and dermatology clinics and who had been taking low dose MTX (< 25 mg/week) for at least 3 months. In addition, the researchers only enrolled participants who had previously received two COVID-19 vaccine doses. The primary outcome of the study was the antibody response against the receptor-binding domain of the COVID-19 spike protein (S1-RBD) 4 weeks after receipt of the third COVID-19 vaccine dose. Secondary outcomes included S1-RBD antibody titres at 12 weeks post-vaccination and self-reported levels of disease activity.

Methotrexate suspension and S1-RBD antibody response

A total of 254 individuals with a mean age of 59.1 years (61% female) were included in the trial and randomised equally to either strategy. Overall, 51% of participants had rheumatoid arthritis, 34% psoriasis and 20% a skin condition alone. The median dose of methotrexate taken as 20 mg/week.

After 4 weeks, the geometric mean SI-RBD antibody titre was 22,750 U/ml in the suspend methotrexate group and 10,798 U/ml in the continue methotrexate group (p < 0.0001). This increase was independent of the dose and administration route of methotrexate, as well as type of immune-mediated inflammatory disease and age. Moreover, this difference in response remained significant at week 12 (16,520 vs 8094).

One downside of the study was that significantly more patients in the suspend methotrexate group self-reported at least one disease flare over the 12 week period compared to those who continued with the drug (71% vs 45%, odds ratio, OR = 2.83, 95% CI 1.64 – 4.88). However, these flares were generally self-managed and without any major impacts on quality of life.

The authors concluded that their strategy of stopping MTX was both safe and boosted the level of COVID-19 antibodies and called for further studies to examine the effect of stopping other immunosuppressant drugs on the level of antibody response.

Abhishek A et al. Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial. Lancet Resp Med 2022

Fourth COVID-19 vaccination superior to third against adverse COVID-19-related outcomes

29th April 2022

A fourth COVID-19 vaccination offers greater protection against adverse COVID-19 outcomes compared to individuals having had only three doses

Having a fourth COVID-19 vaccination at least four months after the third dose, offers better short-term protection against COVID-19-related adverse outcomes compared to only three doses of the vaccine. This was the main finding of a study by Israeli researchers from the Clalit Research Institute, Innovation Division, Tel-Aviv, Isreal.

Whilst millions of individuals have now received at least three doses of a COVID-19 vaccine, there is evidence that with the emergence of variants such as Omicron, vaccine effectiveness wanes over time. This was observed, for example, in one US study, during the Omicron period. The authors found that vaccine effectiveness against emergency department visits was 87% during the first 2 months after a third dose but decreased to 66% among those vaccinated 4-5 months earlier. In fact, it is already apparent, albeit from a single study, that the rates of confirmed COVID-19 infection and severe illness were lower after a fourth dose of BNT162b2 vaccine compared to after only three doses. Whilst this is an important finding, to date, the effectiveness of a fourth COVID-19 vaccination against other outcomes of interest such as hospitalisation and deaths remains uncertain.

For the present study the Israeli team examined the relative effectiveness of four compared to three doses of vaccine among those aged 60 years and older who had received a third dose at least 4 months earlier.

Using data contained within the Clalit Health Services, which is the largest payer-provide organisation in Israel, the team included patients deemed eligible for a fourth dose and who had no previously recorded infection with COVID-19. There were a total of 5 outcomes of interest: COVID-19 infection; symptomatic COVID-19, COVID-19-related hospitalisation, severe COVID-19 and COVID-19-related death. All of these outcomes were assessed 7 to 30 days after the fourth COVID-19 vaccination and 14 to 30 days after vaccination. Those who received a fourth vaccine dose were matched with individuals who had only received three doses and with similar co-morbidities.

Fourth COVID-19 vaccination and adverse COVID-19-related outcomes

A total of 182,122 individuals who received a fourth vaccination dose and a median age of 72 years (53% female) were matched with a group of control patients (three vaccine doses).

During days 7 to 30, the estimated relative effectiveness of the fourth COVID-19 vaccination compared to three doses was 45% against a PCR confirmed COVID-19 infection, 55% against symptomatic COVID-19, 68% against COVID-19 hospitalisation and 74% against COVID-19-related mortality. Moreover, these effectiveness values were broadly similar when assessed 14 to 30 days after the fourth dose.

The authors discussed how use of a fourth dose appeared to be effective against the Omicron variant which was the main circulating variant at the time of the study (January 3 to February 18, 2022). They concluded that a fourth COVID-19 vaccination dose provided additional protection compared to only three doses in those older than 60 years of age.

Magen O et al. Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting New Eng J Med 2022

Seroconversion rates low after COVID-19 vaccination among immunocompromised

18th March 2022

Seroconversion rates among immunocompromised patients are low after the first COVID-19 vaccine dose but increase upon receipt of the second

Seroconversion rates after a single COVID-19 vaccination among immunocompromised patients is low but improves after a second dose according to the findings of a systematic review and meta-analysis by researchers from the Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Immunocompromised patients are at an increased risk severe COVID-19 illness and death. Moreover, it is recognised that among immunocompromised, solid organ transplant patients, a wide range of respiratory viruses cause significant morbidity and mortality among transplant recipients. In a 2020 review of COVID-19 in cancer patients, it was noted how those with cancer are susceptible to severe clinically adverse events and a higher mortality from COVID-19 infection as well as morbidity and mortality from their underlying malignancy. Although one 2018 systematic review found that  seroconversion and sero-protection rates for influenza antigens were low in solid organ transplant recipients, no such reviews on the immunogenicity of COVID-19 vaccines and the overall seroconversion rates among cohorts of immunocompromised patients and been undertaken.

For the present study, the Singaporean team compared the seroconversion rates among groups of immunocompromised patients compared to immunocompetent controls. The team searched for studies that included patients with active cancer of solid organs, haematological cancers, organ transplant recipients, those with active immune mediated inflammatory disorders and for which a comparator group was included. The primary outcomes of interest were seroconversion after the first and second COVID-19 vaccine doses.

Seroconversion rates after vaccination

A total of 82 studies were included in the meta-analysis.

Among those with haematological cancers, compared to immunocompetent individuals, the seroconversion rate after the first vaccination was less than half (risk ratio, RR = 0.40, 95% CI 0.32 – 0.50) and similar for those with solid cancers (RR = 0.55, 95% CI 0.46 – 0.65) and immune mediated inflammatory disorders (RR = 0.53, 95% CI 0.39 – 0.71). However, it was significantly lower for organ transplant patients (RR = 0.06, 95% CI 0.04 – 0.09).

After the second vaccination, the rates of seroconversion increased. For example, for haematological cancers (RR = 0.63) and among those with solid cancer (RR = 0.90) and whilst higher, remained very low, among organ transplant patients (RR = 0.39).

The authors did not include studies where a third COVID-19 dose had been administered in the meta-analysis because most studies did not include a comparator for control purposes. Nevertheless, based solely on a systematic review, they found that conversion rates for organ transplant patients improved by 36 and 66.7%.

The authors concluded that administration of a third vaccine dose (which has now become standard practice for everyone) is warranted for immunocompromised patients.

Lee ARYB et al. Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis BMJ 2022