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14th October 2022
Exposure to some recently identified COVID-19 variants pose an increased risk for developing COVID-19 according to the US food and drug administration (FDA). The release warns that health care professionals should inform patients of this risk and advise patients who develop signs or symptoms of COVID-19 to get tested and promptly seek medical attention, including starting treatment for COVID-19, as appropriate if they test positive.
Evusheld consists of a 300mg dose of both tixagevimab and cilgavimab that are administered as two separate, sequential IM injections. According to its summary of product characteristics, the combination is indicated for the pre-exposure prophylaxis of COVID-19 in adults who are not currently infected with the virus and who have not had a known recent exposure to a COVID-19 infected individual infected and who are unlikely to mount an adequate immune response to a COVID-19 vaccination or where vaccination is not recommended. Data from the TACKLE study showed that a single intramuscular tixagevimab-cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death compared to placebo in unvaccinated individuals.
Over time as the COVID-19 virus has mutated, several COVID-19 variants have emerged in particular, the omicron variant which has been divided into five distinct sub-lineages: BA.1, BA.2, BA.3, BA.4, and BA.5. A major concern has therefore been whether existing therapies are still capable of neutralising these emerging variants. Thankfully, studies in mice has shown that Evusheld (AZD7442) retains neutralising activity against the Omicron lineage strains BA.1, BA.1.1 and BA.2. However, as more variants emerge, the latest FDA update suggests that certain COVID-19 variants may not be neutralised by monoclonal antibodies such as tixagevimab and cilgavimab (i.e., Evusheld).
COVID-19 variants and Evusheld neutralisation
The update includes in vitro neutralisation data showing that there is a greater than 1000-fold reduction in susceptibility for the COVID-19 variant BA.4.6 with Evusheld and data from the CDC in the US currently shows that BA4.6 represents 12.8% of the circulating variants of concern.
The FDA also adds that ‘the use of Evusheld is not a substitute for COVID-19 vaccination and individuals for whom COVID-19 vaccination is recommended should get vaccinated.’ Despite this the FDA continues to recommend Evusheld as an appropriate option for pre-exposure prophylaxis to prevent COVID-19, in combination with other preventative measures like getting vaccinated and boosted as recommended. This is because Evusheld still offers protection against many of the currently circulating variants and may offer protection against future variants.
13th January 2022
Vaccination has been found to result in a smaller reduction in the transmission of the Delta compared to the alpha variant according to a study by researchers from Oxford University, UK.
Vaccination against COVID-19 has been shown to reduce symptomatic infection and even onward transmission of the virus among household contacts. Furthermore, some data indicates that this reduced risk of onward transmission is because of a lower viral load among vaccinated individuals although other evidence points to a similar viral load among those who are vaccinated but infected with the Delta variant.
For the present study, the Oxford team used national contact testing data in England for adults (> 18 yeas of age) with both symptomatic and asymptomatic infections. Their analysis included vaccination with either BNT162b2 or ChAdOx1 to investigate differences in transmission from index patients infected with either variant. The analysis included regression models to determine any associations between onward transmission and the vaccination status of the index patient.
Findings
Among 146,243 tested contacts from a total of 108,498 index patients, with a median age of 34 years (51% female), 37% had a positive PCR test.
Using regression modelling, among index patients doubly vaccinated with BNT162b2 and who became infected, there was a significantly reduced risk of onward transmission of the Alpha variant (adjusted rate ratio, aRR = 0.32, 95% CI 0.21 – 0.48) compared unvaccinated individuals. Similarly, those with two vaccinations of ChAdOx1, also had a reduced risk of onward transmission (aRR = 0.48, 95% CI 0.30 – 0.78) compared to the unvaccinated.
In contrast, the extent of onward transmission of the Delta variant was reduced compared to Alpha by both vaccines but was greater among those doubly vaccinated with BNT162b2 (aRR = 0.50, 95% CI 0.39 – 0.65) compared to ChAdOx1 (aRR = 0.76, 95% 0.70 – 0.82). In other words, index patients vaccinated with BNT162b2 were less likely to have contacts with a positive PCR test for Delta compared to those given the ChAdOx1 vaccine.
The Delta variant was also associated with more onward transmission from both symptomatic index patients (aRR = 1.24, 95% CI 1.12 – 1.38) and from asymptomatic individuals (aRR = 1.40, 95% CI 1.22 – 1.59) and this was independent of both index and contact vaccination status.
Interestingly, the risk of infection with the Alpha variant among fully vaccinated contacts, was much lower among those given BNT162b2 (aRR = 0.15, 95% CI 0.11 – 021) compared to those fully vaccinated with ChAdOx1 (aRR = 0.40, 95% CI 0.27 – 0.59) and the magnitude of these reductions were similar for infections with the Delta variant.
Both symptomatic and asymptomatic index patients infected with the Delta variant had lower Ct values (i.e., higher viral loads) compared to those infected with the Alpha variant. When including Ct values in their regression models, the authors reported that lower Ct values were independently associated with increased transmission of either variant.
The authors concluded that vaccination was associated with a smaller reduction in transmission of the Delta compared to the Alpha variant.
Citation
Eyre DW wt al. Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants. N Eng J Med 2022.
5th January 2022
A third COVID-19 vaccine dose appears, in practice, to be unlikely to offer much protection against the Omicron compared with the Delta variant. This was the finding of a preprint from a large Canadian study by a team led by Public Health Ontario, Toronto, Canada.
The Omicron COVID-19 variant was first reported to the World Health Organization (WHO) from South Africa on 24 November 2021 and the WHO has since designed it as a variant of concern due to an increased transmissible nature and the potential for immune evasion.
Moreover, early data suggests that while a third COVID-19 vaccine dose offers higher protection against Omicron, the authors added that ‘even with three vaccine doses, neutralisation against the omicron variant was lower (by a factor of 4) than that against the delta variant.’
In trying to provide some much needed data on the real-world effectiveness of vaccine effectiveness (VE) against the Omicron or Delta variant, the Canadian team examined individuals 18 years and over, with a positive PCR test result between November 2021 and December 2021, excluding long-term residents and those who had received only a single COVID-19 vaccine dose or a second dose less than 7 days prior to testing.
The researchers identified confirmed cases of infection, irrespective of symptoms or severity using provincial reportable data. Any positive samples with an S-gene Target failure (SGTF), were considered to be due to infection with Omicron since this failure is absent in those with the Delta variant.
They compared infection rates (compared to those who were unvaccinated and which served as the reference group) for individuals with either two or a third COVID-19 vaccine dose.
Findings
The team identified 3,442 Omicron positive, 9,201 Delta positive and 471,545 negative controls. Omicron infected individuals were generally younger, mean age 34.8 years (49.2% male) compared to 43.7 years (same gender proportion) for Delta infections.
After two doses of a COVID-19 vaccine, VE efficacy against Delta was 71% (95% CI 66 – 75%) > 240 days after the second dose but this figure increased to 93% (95% CI 92 – 94%) > 7 days after a third dose.
In contrast, two vaccine doses was not protective against Omicron at any point in time and the VE was – 38% (95% CI – 61 to – 18%) after the second dose.
However, VE against Omicron was 37% (95% CI 19 – 50%) > 7 days after a third COVID-19 vaccine and these findings were consistent for all combinations of the vaccines used.
The authors discussed how their findings have potentially important implications in so far as proof of vaccination (defined by at least two doses) should no longer be considered as fully vaccinated.
They concluded that protection from three vaccine doses offers some protection against the variant but the effectiveness against severe disease remains uncertain.
Citation
Buchan SA et al. Effectiveness of COVID-19 vaccines against Omicron or Delta infection MedRxiv 2021.
13th December 2021
In a press release, Pfizer and BioNTech have announced that serum antibodies induced after three doses of their COVID-19 vaccine (BNT162b2) are able to neutralise the Omicron variant.
The company’s laboratory study involved testing human sera obtained from the blood of individuals who had received two or three 30-µg doses of the BNT162B2 using a pseudovirus neutralisation test, which used to study the effect of antibodies to neutralise the capability of viruses to enter cells and thus prevent infection. The sera were collected from subjects 3 weeks after receiving the second dose or one month after receiving the third dose of their vaccine
In the study, each sample of serum was simultaneously tested for its neutralising antibody titre against the original (or wild-type) COVID-19 spike protein as well as the Omicron spike variant. The researchers found that after a third vaccine dose, there was a significant, 25-fold increased level of neutralising antibody titres against the Omicron strain spike protein. In fact, antibody titre levels against the Omicron variant were comparable to the neutralisation against the wild-type strain observed in sera from individuals who received two doses of the companies’ COVID-19 vaccine. However, data on the persistence of these neutralising antibodies over time is uncertain and will be determined over time.
At the present time, there is still much to learn about the Omicron variant although a preliminary study from South Africa in 12 people has provided some answers. The study included 12 individuals with a mean age of 57 years (66% male), 6 of whom had been vaccinated with the remaining 6 having been both vaccinated and previously infected. The purpose of the study was to examine whether the Omicron variant still required the ACE2 receptor to gain entry to cells and if plasma from those vaccinated with BNT162b2 were able to neutralise the variant. The results showed that the ACE2 receptor was still required to gain entry to cells but also that there was a 41-fold reduction in antibody neutralisation against Omicron compared with the original wild-type. However, on the plus side, escape was much less in those who had been previously infected the COVID-19.
There is still much to learn about the Omicron variant, in particular its transmissibility and whether it results in more severe infections and hospitalisations.
However, one point reassuring point mentioned in Pfizer-BioNTech press release was how 80% of the regions of the spike protein that are recognised by cytotoxic (killer) T (CD8 +) cells are unchanged in the variant. It is possible therefore, that three doses, i.e., full vaccination and a booster, will hopefully provide an enhanced immune response and which may be sufficient to prevent the variant from causing more severe disease.
8th December 2021
mRNA-1273 appears to be associated with a lower risk of COVID-19-related outcomes such as infection, hospitalisation and death compared to BNT162b. This was the finding of the first head-to-head vaccine effectiveness analysis undertaken by a group of researchers from the Brigham and Women’s Hospital, Harvard Medical School, Boston, US.
Randomised controlled trials have already demonstrated the effectiveness of the currently available COVID-19 vaccines. For instance, the mRNA-1273 vaccine (Moderna) has an efficacy of 94.1% at preventing COVID-19 illness and that a similar efficacy (95%) has been observed for BNT162b (Pfizer-BioNTech).
However, despite this near identical level of efficacy, other work has suggested that there might be differences between these two vaccines, even though they have the same mode of action. One study, for example, indicated that the mRNA-1273 vaccine produced a higher humoral immunogenicity than BNT162b, while other data show that the Moderna vaccine it is associated with a two-fold reduced risk of breakthrough infections compared to BNT162b and also results in a lower incidence of COVID-19-related hospitalisations.
For the present study, the US team turned to data from the national healthcare databases of the Department of Veterans Affairs, which is the largest US integrated healthcare system. The researchers sought to compare the relative effectiveness of the Moderna and Pfizer-BioNTech vaccines with respect to documented COVID-19 infections, symptomatic COVID-19, hospitalisation, admission to an intensive care unit (ICU) and death. In addition, the team examined the effectiveness of the two vaccines against the delta COVID-19 variant and examined these outcomes after 24 weeks.
Findings
During the period of study, there were 367,113 recipients of the BN162b and 397,690 of the mRNA-1273 vaccines. Over a 24-week period, 2016 COVID-19 infections were documented, of which 559 were detected as symptomatic, 411 which led to hospitalisation, 125 ICU admissions and 81 deaths.
The absolute risk of infection was low in both vaccine groups; 5.75 events per 1000 persons with the Pfizer-BioNTech and 4.52 with the Moderna vaccine. The 24 week risk ratio for infections for BNT162b compared to mRAN-1273 was 1.27 (95% CI 1.15 – 1.42), 1.39 for symptomatic infection, 1.70 for hospitalisation, 1.38 for ICU admission and 1.11 for death. Each of these risks was statistically significant apart from the risk of death. The overall risk difference expressed as events over 24 weeks per 1,000 persons was 1.23 for a documented infection.
Using these data, the authors calculated the number needed to vaccinate with mRNA-1273 instead of BN162b to prevent one case of documented infection was 813.
Analysis during the time period characterised by dominance of the delta COVID-19 variant, there was a 58% higher risk of infection in those vaccinated with BNT162b although this difference was non-significant (risk ratio = 1.58, 95% CI 0.85 – 2.33).
Commenting on these findings, the authors highlighted how their study had shown that recipients of the BNT162b vaccine had a 27% higher risk of a documented COVID-19 infection and a 70% increased risk of hospitalisation compared to the Moderna vaccine.
They concluded that the data provided evidence of a lower 24-week risk of COVID-19-related outcomes among those receiving the m-RNA-1273 vaccine compared to BNT162b.
Citation
Dickerman BA et al. Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans. New Eng J Med 2021
16th August 2021
Vaccines against COVID-19 have been administered across the globe and have been shown to be efficacious at preventing COVID-19 illness. However, with the emergence of viral variants, some of which are able to escape neutralising antibodies, there is an increased risk of vaccine breakthrough infections. While it is possible to modify existing vaccines to ensure that they are effective against variants of concern, an alternative strategy is to provide individuals with a third, or booster vaccination dose. In fact, there is animal data to suggest that a booster dose increases antibody titres to at least one variant of concern although whether this strategy will be effective in humans remains uncertain. One way of studying the value of a booster dose, is to compare the antibody response generated after full vaccination among those with and without prior infection. This was the objective of a study by a team from the Wolfson Centre for Global Virus Research, University of Nottingham, UK. They used data from the PANTHER Study which is designed to track frontline healthcare workers. For the present study, the researchers were interested in any differences in the antibody response among fully vaccinated individuals, in those with or without a prior COVID-19 infection. Participants were split into two groups (prior or no prior infection) and blood samples taken for analysis of IgG antibody levels to the wild-type COVID-19 and against two variants of concern, B.1.351 and P1 after both their first and second doses of vaccine which were given 10 weeks apart.
Findings
The total cohort consisted of 45 individuals with a mean age of 47.5 years (80% female) and 20 with a prior infection, all of whom had received two doses of BNT162b. The level of antibodies among individuals with a prior infection were higher after a single vaccine dose compared to previously uninfected participants. Interestingly, after the second vaccine dose, there was a significantly increased antibody response, not just to the wild-type COVID-19, but to the two variants of concern among those who had a prior infection compared with uninfected individuals.
Commenting on these findings, the authors suggested that their data showed how repeated exposure to COVID-19, i.e., through a prior infection and two doses of a vaccine, increased the level of neutralising antibodies. In other words, a prior infection much like a booster dose. Furthermore, it was also apparent that this increased antigenic exposure appeared to broaden an individual’s antibody response by creating neutralising antibodies to the two variants of concern. If confirmed in future studies, these results would be of enormous importance. For instance, if repeated exposure not only enhanced but extended immunity against variants of concern, there is a very strong argument for giving individuals a further, third, booster vaccine dose, even if this is directed at the original spike protein, to combat any new variants likely to emerge in the future.
Citation
Urbanowicz RA et al. Two doses of the SARS-CoV-2 BNT162b2 vaccine enhances antibody responses to variants in individuals with prior SARS-CoV-2 infection. Sci Transl Med 2021
5th August 2021
There is now clear evidence that vaccination against COVID-19 reduces symptom burden and duration of any associated illness. An emerging problem is the appearance of new COVID-19 variants, in particular, the COVID delta variant. However, an analysis by Public Health England, has shown that two doses of a COVID-19 vaccine, reduces the incidence of hospitalisation in those infected with the delta variant. Furthermore, in the US, the Centers for Disease Control and Prevention (CDC) produced updated advice indicating how a body of evidence now suggests that full vaccinated individuals were less likely to either acquire COVID-19 or transmit the virus onto others. However, despite this, there are emerging concerns, particularly from Israel, which has managed to vaccinate a large proportion of the adult population, that the reported effectiveness of COVID-19 vaccines has reduced to 64% with regard to preventing infection and symptomatic illness. Interestingly, this reduced effectiveness appears to coincide with the spread of the COVID delta variant in the country. This is of particular concern given how it is thought that the COVID delta variant has an estimated 60% higher risk of household transmission. Thus, some uncertainty remains over the effectiveness of vaccines against the COVID delta variant and the extent to which the risk of transmission is reduced.
Potential for increased transmission
In light of this uncertainty, the CDC has released data captured from an outbreak of COVID-19 during July 2021, associated with large, public gatherings, in Massachusetts. During the month of July, 469 cases of COVID-19 associated with multiple summer events and public gatherings were reported. The reported vaccination coverage among eligible Massachusetts residents was 69% although the majority (74%) of symptomatic infected cases occurred in fully vaccinated individuals, who had received either the Pfizer-BioNTech or Jansen vaccine. Most infections (85%) occurred in males with a median age of 40 years.
A total of 133 patients provided samples for genomic analysis, of which, 89% were due to the COVID delta variant. Fortunately, only five people required hospitalisation (four who were fully vaccinated) and no deaths were reported. PCR cycle threshold (CT) values, which represent a measure of the concentration of viral load present in a sample, were taken from 127 vaccinated and 84 unvaccinated individuals. The lower the CT value, the more viral material present and the median CT values were 22.77 and 21.54 for the vaccinated and unvaccinated individuals respectively. In order words, given that the transmissibility of COVID-19 is known to be dependent on viral load, it would appear that the infection with the COVID delta variant, even among fully vaccinated individuals, could still lead to appreciable transmission of the virus. As a result of these findings, the CDC has now suggested that prevention strategies such as mask wearing should continue indoors, irrespective of vaccination status.
7th June 2021
As mutations enable the emergence of COVID-19 variants, it is crucial to determine if the available vaccines are able to induce a satisfactory level of neutralising antibodies (NAbs) against any new variants. In a laboratory study, a team from the Francis Crick Institute and the National Institute for Health Research, set out to assess the level of NAbs produced in response to five COVID-19 variants, including the original viral strain as well as three others that have been deemed variants of concerns; B.1.167.2 (Delta or Indian variant), B.1.351 (South African variant) and the B.1.1.7 (UK variant). They also compared the level of NAbs produced in participants who had received either one or two doses of the BNT162b vaccine.
Findings
Among 159 participants who had received both doses of the vaccine, all samples produced a satisfactory NAbs response against each of the strains although six and nine individuals lacked detectable antibodies against the B.1.617.2 and B.1.351 respectively. However, despite the induction of NABs, levels were 5.8-fold less against the Delta variant compared with the original strain and 2.6-fold less against the B.1.1.7 although of a similar order of magnitude for the B.1.351. Interestingly, there was a significant correlation between NAbs and age, with titres significantly reduced among older individuals. A further finding of concern was that among a smaller cohort (14), who had been vaccinated between 8 and 16 weeks earlier, there was a significant reduction in NAbs titre against all of the variants.
Perhaps of most interest were the data from participants who had received only a single vaccine dose. After a median of 30 days post-vaccination, 79% of individuals had sufficient NAbs against the original strain, but this reduced to 50% for B.1.1.1, 32% for B.1.617.2 and to 25% for B.1.351.
In a discussion of these findings, the authors suggested that although NAbs levels are considerably reduced against the B.1.617.2 and B.1.351 after a single vaccination, this emphasised the importance of reducing the delay period (which has been set at 12 weeks) between doses.
Lead author of the study Emma Wall, said “This virus is likely to be around for some time to come, so we need to remain agile and vigilant. Our study is designed to be responsive to shifts in the pandemic so that we can quickly provide evidence on changing risk and protection”.
Citation
Wall EC et al. Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet 2021
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