Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England: matched cohort examine in OpenSAFELY-TPP

Goal To check the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) covid-19 vaccines throughout the booster programme in England.

Design Matched cohort examine, emulating a comparative effectiveness trial.

Setting Linked main care, hospital, and covid-19 surveillance data out there throughout the OpenSAFELY-TPP analysis platform, overlaying a interval when the SARS-CoV-2 delta and omicron variants have been dominant.

Contributors 3 237 918 adults who obtained a booster dose of both vaccine between 29 October 2021 and 25 February 2022 as a part of the nationwide booster programme in England and who obtained a main course of BNT162b2 or ChAdOx1.

Intervention Vaccination with both BNT162b2 or mRNA-1273 as a booster vaccine dose.

Fundamental consequence measures Recorded SARS-CoV-2 optimistic check, covid-19 associated hospital admission, covid-19 associated loss of life, and non-covid-19 associated loss of life at 20 weeks after receipt of the booster dose.

Outcomes 1 618 959 folks have been matched in every vaccine group, contributing a complete 64 546 391 particular person weeks of follow-up. The 20 week dangers per 1000 for a optimistic SARS-CoV-2 check have been 164.2 (95% confidence interval 163.3 to 165.1) for BNT162b2 and 159.9 (159.0 to 160.8) for mRNA-1273; the hazard ratio evaluating mRNA-1273 with BNT162b2 was 0.95 (95% confidence interval 0.95 to 0.96). The 20 week dangers per 1000 for hospital admission with covid-19 have been 0.75 (0.71 to 0.79) for BNT162b2 and 0.65 (0.61 to 0.69) for mRNA-1273; the hazard ratio was 0.89 (0.82 to 0.95). Covid-19 associated deaths have been uncommon: the 20 week dangers per 1000 have been 0.028 (0.021 to 0.037) for BNT162b2 and 0.024 (0.018 to 0.033) for mRNA-1273; hazard ratio 0.83 (0.58 to 1.19). Comparative effectiveness was typically comparable inside subgroups outlined by the first course vaccine model, age, earlier SARS-CoV-2 an infection, and medical vulnerability. Relative profit was comparable when vaccines have been in contrast individually within the delta and omicron variant eras.

Conclusions This matched observational examine of adults estimated a modest good thing about booster vaccination with mRNA-1273 in contrast with BNT162b2 in stopping optimistic SARS-CoV-2 exams and hospital admission with covid-19 20 weeks after vaccination, throughout a interval of delta adopted by omicron variant dominance.

Knowledge sources

All information have been linked, saved, and analysed securely throughout the OpenSAFELY platform (https://opensafely.org/). With the approval of NHS England, main care data managed by the overall follow software program supplier TPP have been linked, utilizing NHS numbers, to emergency division attendance and inpatient hospital spell data by way of NHS Digital’s Hospital Episode Statistics, nationwide coronavirus testing data by way of the Second Era Surveillance System (SGSS), and nationwide loss of life registry data from the Workplace for Nationwide Statistics. Covid-19 vaccination historical past and well being and social care employee standing can be found within the basic follow document immediately by way of the Nationwide Immunisation Administration System. The provision of free polymerase chain response (PCR) and lateral stream exams for SARS-CoV-2 in England ended on 31 March 2022, so we didn’t use testing information after this date.

Vaccination methods

The 2 methods of curiosity have been a 3rd vaccine dose of BNT162b2 or mRNA-1273. We didn’t try to differentiate between third main doses and first booster doses, as this data is just not unambiguously ascertainable within the well being document. Nonetheless, most recipients of a 3rd main dose could have had their third dose earlier than the examine interval.

Eligibility standards

Individuals who obtained a 3rd dose of BNT162b2 or mRNA-1273 between 29 October 2021 and 25 February 2022 inclusive, throughout which era each vaccine manufacturers have been getting used, have been thought-about for inclusion and categorized within the corresponding group. Third dose recipients have been eligible in the event that they have been aged 18 years and over; have been registered at a basic follow utilizing TPP’s SystmOne medical data system on the time of boosting; obtained a two dose main vaccination course of both BNT162b2 or ChAdOx1-S (we didn’t think about combined dosing and mRNA-1273 owing to small numbers); weren’t a well being or social care employee, not resident in a care or nursing residence, and never medically housebound or receiving end-of-life care; had no proof of SARS-CoV-2 an infection or covid-19 throughout the earlier 28 days; weren’t admitted to hospital on the time of boosting; and had full data on intercourse, deprivation, and Sustainability and Transformation Partnership (STP, a geographical grouping of NHS and native authorities).

Matching

We matched BNT162b2 and mRNA-1273 recipients one to at least one with out alternative on the next traits: date of third dose (precisely), main vaccine course (BNT162b2 or ChadOx1-S), date of second vaccine dose (seven day caliper), intercourse (male or feminine), age (three 12 months caliper and inside age teams outlined by JVCI danger teams), medical danger group outlined by JCVI (clinically extraordinarily weak, clinically in danger, neither); Index of A number of Deprivation (grouped by fifths), STP as a surrogate for geographical area, proof of earlier SARS-CoV-2 an infection (any of optimistic SARS-CoV-2 check, possible an infection documented in main care, or covid-19 associated hospital attendance or admission), and morbidity depend (grouped as no, one, or two or extra situations from the next record: diabetes, physique mass index >40, continual coronary heart illness, continual kidney illness, continual liver illness, continual respiratory illness or extreme bronchial asthma, continual neurological illness, most cancers inside three years). No values have been lacking for these variables; we excluded folks with lacking values for age, intercourse, Index of A number of Deprivation, or STP (2.8% of all adults receiving a 3rd dose throughout the examine interval; see determine 1), and we outlined all different variables by the presence or absence of medical codes or occasions. The supplementary supplies present extra data on how these traits have been chosen and outlined.

Outcomes and follow-up

We thought-about three covid-19 associated outcomes. We recognized optimistic SARS-CoV-2 exams through the use of SGSS testing data and on the idea of swab date. We used the primary optimistic check after baseline, no matter whether or not this was the primary ever optimistic check for every particular person. We included each PCR and lateral stream check outcomes, with out differentiating between symptomatic and asymptomatic an infection. As each PCR exams and lateral stream exams are extremely particular, we don’t think about unfavourable exams across the identical time to undermine the conclusiveness of a optimistic check. We recognized covid-19 associated hospital admission through the use of Secondary Use Service inpatient hospital data with ICD-10 (worldwide statistical classification of ailments, tenth revision) codes U07.1, U07.2, or U.909 as the first or non-primary cause for admission. We outlined covid-19 associated loss of life as loss of life with U07.1, U07.2, or U.909 ICD-10 codes talked about wherever on the loss of life certificates (that’s, as an underlying or contributing reason behind loss of life). We additionally report on non-covid-19 associated deaths.

We adopted every particular person from receipt of a 3rd vaccine dose (time zero) till the end result of curiosity, with censoring at loss of life, follow de-registration, 28 weeks, or the follow-up finish date, which was 31 March 2022 for optimistic SARS-CoV-2 exams (coinciding with the tip of freely out there neighborhood testing in England) and 1 July 2022 in any other case.

Statistical evaluation

We tabulated baseline traits of every vaccine group and examined between group steadiness through the use of standardised imply variations. We estimated the cumulative incidence of every consequence in every vaccine group through the use of the Kaplan-Meier estimator. We estimated cumulative danger variations and danger ratios evaluating the vaccine teams for every consequence. These have been estimated as much as 28 weeks the place out there, however we report estimates at 20 weeks as the first comparability owing to the truncated follow-up for SARS-CoV-2 exams. We additionally used Cox fashions to estimate hazard ratios over the primary 20 weeks and inside interval particular intervals outlined by splits on weeks 1, 2, 4, 8, 12, 16, 20, 24, and 28, the place out there.

We used normal errors on the log-Kaplan-Meier scale to derive 95% confidence limits for the cumulative incidences. We derived confidence limits for the chance variations from the sum of squares of the usual errors on the Kaplan-Meier scale, utilizing Greenwood’s formulation. We derived confidence limits for the chance ratio from the sum of squares of the usual errors on the log-Kaplan-Meier scale.

Affected person and public involvement

Public contributors weren’t concerned in setting the analysis query or the end result measures, nor in creating plans for design or implementation of the examine. No public contributors have been requested to advise on interpretation or writing up of outcomes. Covid-19 vaccination is obtainable to the entire inhabitants, together with the researchers concerned within the examine.

Examine inhabitants and matching

A complete of 10 443 504 adults registered at a TPP follow obtained a 3rd vaccine dose of both BNT162b2 (7 455 429) or mRNA-1273 (2 988 075) throughout the examine interval, with 6 721 857 (90.2%) and a pair of 719 653 (91.0%) eligible for matching (fig 1). Eligible BNT162b2 third dose recipients have been on common older and extra disadvantaged and had increased charges of earlier medical situations than mRNA-1273 third dose recipients (supplementary desk S1). They have been additionally extra prone to have obtained BNT162b2 as their main vaccination course (38% v 30%).

After matching, 1 618 959 folks in every vaccine group (whole 3 237 918) have been included in analyses, representing 24.1% and 59.5% of eligible BNT162b2 and mRNA-1273 recipients respectively (fig 1 and supplementary determine S1). Traits in the beginning of follow-up have been effectively balanced between teams (desk 1), with standardised imply variations persistently beneath 0.05 (supplementary determine S2 and desk S1). Particularly, earlier medical situations, which weren’t immediately matched on, have been effectively balanced between the teams after, though not earlier than, matching. The entire follow-up time throughout each teams was 64 546 391 particular person weeks. The median follow-up was 15.3 weeks for optimistic SARS-CoV-2 exams and 28.0 weeks for different outcomes (supplementary desk S3). SARS-CoV-2 testing charges after baseline have been barely much less frequent for BNT162b2 than for mRNA-1273 (0.139 v 0.151 per week respectively; supplementary desk S4).

Estimated comparative effectiveness

By 20 weeks, 412 038 optimistic SARS-CoV-2 exams, 2250 covid-19 associated hospital admissions, and 84 covid-19 associated deaths had occurred (desk 2). The 20 week dangers (cumulative incidence) per 1000 folks of a optimistic SARS-CoV-2 check have been 164.2 (95% confidence interval 163.3 to 165.1) for these receiving BNT162b2 and 159.9 (159.0 to 160.8) for mRNA-1273 (danger distinction −4.25, 95% confidence interval −5.53 to −2.98) (desk 2; fig 2). The corresponding 20 week dangers per 1000 folks for covid-19 associated hospital admission have been 0.75 (0.71 to 0.79) for BNT162b2 and 0.65 (0.61 to 0.69) for mRNA-1273 (danger distinction −0.10, −0.16 to −0.046). The 20 week dangers per 1000 folks of covid-19 associated loss of life have been 0.028 (0.021 to 0.037) for BNT162b2 and 0.024 (0.018 to 0.033) for mRNA-1273 (danger distinction −0.004, −0.015 to 0.007). Corresponding dangers of non-covid-19 associated loss of life have been 0.67 (0.63 to 0.71) for BNT162b2 and 0.59 (0.56 to 0.63) for mRNA-1273 (danger distinction −0.078, −0.13 to−0.023).

Fig 2

Estimates of cumulative danger per 1000 folks (left plots) and cumulative danger ratios (proper plots)

For optimistic SAR-CoV-2 exams, the cumulative danger ratio evaluating mRNA-1273 with BNT162b2 reached a minimal of 0.91 (95% confidence interval 0.90 to 0.92) at 4 weeks after which attenuated with rising follow-up (fig 2). For covid-19 associated hospital admission, the minimal danger ratio was 0.67 (0.59 to 0.76) at round 11 weeks, attenuating to 0.89 (0.83 to 0.96) by 28 weeks. The variety of covid-19 associated deaths was too small for us to have the ability to reliably study patterns of cumulative incidence over time. For non-covid-19 associated loss of life, the chance ratio was imprecisely estimated within the first few weeks however stabilised to 0.92 (0.86 to 0.99) at 28 weeks. Hazard ratios (whereby <1 favours mRNA-1273) within the 20 week interval after receipt of third dose have been 0.95 (95% confidence ratio 0.95 to 0.96) for optimistic SARS-CoV-2 check, 0.89 (0.82 to 0.95) for covid-19 associated hospital admission, 0.83 (0.58 to 1.19) for covid-19 associated loss of life, and 0.92 (0.86 to 0.99) for non-covid-19 associated loss of life (fig 3 and fig 4).

Fig 3

Estimated hazard ratios at 20 week follow-up evaluating effectiveness of mRNA-1273 and BNT162b2 on SARS-CoV-2 an infection and covid-19 associated hospital admission, general and inside subgroups, along with P values for between subgroup heterogeneity. CI=confidence interval

Fig 4

Estimated hazard ratios at 20 week follow-up evaluating effectiveness of mRNA-1273 and BNT162b2 on covid-19 associated and non-covid-19 associated loss of life, general and inside subgroups, along with P values for between subgroup heterogeneity. CI=confidence interval

Interval particular hazard ratios are proven in supplementary determine S4a. In the course of the first week after vaccination, occasion charges have been comparable between vaccine teams: the estimated hazard ratio was 0.99 (0.97 to 1.01) for optimistic SARS-CoV-2 exams, 0.86 (0.54 to 1.39) for covid-19 associated hospital admission, 1.00 (0.06 to fifteen.99) for covid-19 associated loss of life, and 0.92 (0.51 to 1.63) for non-covid-19 associated loss of life. After this preliminary interval, the speed for optimistic SARS-CoV-2 exams was decrease for mRNA-1273 than BNT162b2 till week 12, after which it was increased for mRNA-1273. For covid-19 associated hospital admission, the minimal hazard ratio was 0.64 (0.53 to 0.79) throughout weeks 5-8, with hazard ratios between 12 and 28 weeks in keeping with no distinction between vaccine teams. For non-covid-19 associated loss of life, hazard ratios have been near 1 throughout weeks 3-28.

Subgroup analyses

Absolute dangers differed between subgroups, and subsequently so did absolutely the danger variations evaluating vaccines, though mRNA-1273 was persistently related to decrease danger than BNT162b2 for optimistic SARS-CoV-2 exams and covid-19 associated hospital admission (desk 2).

For optimistic SARS-CoV-2 exams, the estimated relative good thing about mRNA-1273 in contrast with BNT162b2 was better in individuals who obtained BNT162b2 for his or her first two vaccine doses (hazard ratio 0.93, 0.92 to 0.94) than in those that obtained ChAdOx1 (0.96, 0.96 to 0.97; P for heterogeneity<0.001) (fig 3). Equally, the estimated relative good thing about mRNA-1273 in contrast with BNT162b2 was better in folks with earlier proof of an infection (hazard ratio 0.93, 0.90 to 0.96) than in these with out (0.95, 0.95 to 0.96; P for heterogeneity=0.066). For covid-19 associated hospital admission, the estimated relative good thing about mRNA-1273 in contrast with BNT162b2 was comparable by sort of first two vaccine doses (hazard ratio 0.86 (0.75 to 1.00) for BNT162b2 and 0.89 (0.82 to 0.97) for ChAdOx1; P for heterogeneity=0.690). The estimated relative good thing about mRNA-1273 was better in folks with earlier proof of an infection (hazard ratio 0.61, 0.42 to 0.89) than in these with out (0.90, 0.84 to 0.97; P for heterogeneity=0.047). For covid-19 associated loss of life, hazard ratios have been estimated imprecisely owing to low occasion charges, so no robust conclusions about variation between subgroups might be made. For non-covid-19 associated loss of life, the relative good thing about mRNA-1273 was typically better in older and extra clinically weak folks.

Supplementary supplies present cumulative incidence plots by subgroup (figures S3a-e); the corresponding cumulative danger variations, cumulative danger ratios, and interval particular hazard ratios (figures S4a-e); and subgroup particular heterogeneity exams for danger variations and danger ratios (desk S2).

Variant period analyses

Hazard ratios estimated for follow-up time restricted to 14 December 2021 (delta period) and restricted to matched pairs who remained in danger on or who have been vaccinated after 15 December 2021 (omicron period) have been comparable or else very imprecisely estimated (supplementary determine S5 and desk S5).

Strengths and limitations of examine

The OpenSAFELY-TPP database covers round 40% of the English inhabitants and comprises wealthy medical data that enabled us to carefully match BNT162b2 and mRNA-1273 recipients to regulate for potential confounding, to review a spread of medical outcomes, together with extreme covid-19, and to check comparative effectiveness between vital medical subgroups.

To make honest comparisons between the 2 vaccine varieties, we exploited the concurrent roll-out of each vaccines throughout the identical eligible inhabitants in the identical time interval. The kind of vaccine administered was primarily based largely on native provide and availability, and medical traits didn’t inform the kind of vaccine supplied on-site. Controlling for any potential variations within the distribution of prognostic components between the 2 vaccine teams remained vital, and these have been effectively balanced after matching. We can’t rule out residual confounding, as we didn’t match on or regulate for all potential confounders—for instance, some medical subgroups through which relative safety might differ between vaccines, akin to immunosuppressive situations. Nonetheless, unmeasured potential confounders, significantly referring to unmeasured well being looking for behaviours, are much less problematic in comparative effectiveness research than in research evaluating vaccinated and unvaccinated folks, as all folks getting into the examine have sought and obtained at three doses of vaccine. Moreover, charges of optimistic SARS-CoV-2 exams have been comparable throughout the first week after vaccination, suggesting that the vaccine teams have been comparable in the beginning of follow-up. We discovered no proof that charges of different outcomes throughout the first week after vaccination differed between the vaccine teams, though a few of these comparisons have been estimated imprecisely.

We excluded teams who have been unlikely to bear boosting, akin to these with a latest optimistic check or in palliative care. We additionally excluded folks dwelling in care houses and well being and social care staff, as these teams are more likely to obtain their vaccines at their place of residence or work somewhat than at walk-in or bookable neighborhood vaccination centres, which can introduce bias. For instance, occupation sort for healthcare staff might affect each setting of vaccine administration (and subsequently vaccine sort) and danger of an infection.

The later introduction of the mRNA-1273 vaccine for the UK booster marketing campaign meant that the matched cohort contained youthful and more healthy folks than the entire inhabitants receiving a 3rd dose, owing to the prioritisation of older folks and people at increased danger. For instance, the variety of folks with immunosuppressive situations within the matched cohort was simply 1.5%. The applicability of our findings to essentially the most weak teams might subsequently be restricted. Nonetheless, numbers remained adequate to check subgroups outlined by age, medical vulnerability, and former an infection standing, together with for covid-19 associated hospital admission.

To regulate for spatiotemporal heterogeneity in danger of an infection throughout the examine interval, we matched on the date of receipt of third dose and native well being administration (STP). Some residual heterogeneity inside STP areas is feasible, however extra exact geographical matching was not possible owing to poor matching success at this stage, partly resulting from time intervals throughout which just one vaccine sort was out there inside a small geographical space.

Some outcomes could also be under-ascertained. Particularly, optimistic SARS-CoV-2 exams embrace solely these reported by way of the nationwide covid-19 surveillance system (SGSS), so many asymptomatic and a few symptomatic infections could have been missed. Publish-baseline SARS-CoV-2 testing charges have been barely increased in mRNA-1273 than in BNT162b2 recipients, which largely guidelines out variations in testing behaviours as an evidence for mRNA-1273’s obvious superiority for stopping optimistic SARS-CoV-2 exams.

This examine doesn’t embrace anybody who obtained mRNA-1273 as a main course owing to low numbers of recipients of this vaccine as a main course. We have been subsequently unable to evaluate whether or not the relative good thing about mRNA-1273 in contrast with BNT162b2 arose due to heterologous boosting with a special vaccine model, as BNT162b2 booster recipients had obtained both BNT162b2 or ChAdOx1first and second vaccine doses. BNT162b2 would possibly outperform mRNA-1273 boosting in individuals who had obtained mRNA-1273 first and second doses. Nonetheless, subgroup analyses in those that obtained ChAdOx1 first and second doses additionally discovered relative good thing about mRNA-1273 over BNT162b2 boosting.

Findings in context

The COV-BOOST part 2 randomised trial assessed the protection and immunogenicity of seven covid-19 vaccines for reinforcing, together with BNT162b2 and mRNA-1273, towards a menACWY management in folks with no earlier historical past of an infection.7 It discovered increased immunogenicity of mRNA-1273 in contrast with BNT162b2 in subgroups with a two dose BNT162b2 main course (geometric imply ratio of SARS-CoV-2 anti-spike IgG versus management 11.49 (95% confidence interval 9.36 to 14.12) versus (6.78 (5.51 to eight.35)) and a two dose ChAdOx1 main course (32.30 (24.84 to 42.01) versus 16.80 (12.97 to 21.76)). Likewise, the MixNMatch part 1-2 non-randomised trial documented increased antibody concentrations after mRNA-1273 enhance than BNT162b2 enhance amongst individuals who obtained a main course of BNT162b2.8 These trials didn’t consider efficacy endpoints, and we’re conscious of no different deliberate or revealed randomised trials making direct comparisons of boosting with BNT162b2 versus mRNA-1273.

A examine in Spanish registry information of individuals aged 40 years or over with no earlier optimistic check for SARS-CoV-2 examined effectiveness of mRNA vaccine boosting, together with a comparability of BNT162b2 with mRNA-1273.9 For optimistic SARS-CoV-2 exams, it estimated a 34 day danger distinction evaluating mRNA-1273 with BNT162b2 of −2.2 (−2.7 to−1.6) per 1000 folks (danger ratio 0.87, 0.84, 0.90). Effectiveness towards hospital admission or different extreme outcomes was not assessed. A examine within the US Veteran Affairs healthcare system within the alpha and delta variant eras utilizing the same matching strategy,10 with 65 196 matched recipients in every vaccine group, reported a 16 week danger ratio of 0.87 (0.77 to 0.94) for documented SARS-CoV-2 an infection, 0.61 (0.36 to 0.79) for covid-19 associated hospital admission, and 0.92 (0.16 to 2.17) for covid-19 associated loss of life.

Comparisons of vaccines for main vaccination in observational information have additionally been made. One other US Veteran Affairs examine by the identical group throughout the alpha interval recognized an extra 1.23 (95% confidence interval 0.72 to 1.81) documented infections per 1000 folks in these with a BNT162b2 first dose in contrast with an mRNA-1273 first dose at 24 weeks, 0.55 (0.36 to 0.83) covid-19 associated hospital admission, 0.10 (0.00 to 0.26) covid-19 associated intensive care unit admissions, and 0.02 (−0.06 to 0.12) covid-19 associated deaths.11 One other examine utilizing Veterans Affairs information with actual matching and propensity matching in the same time interval estimated comparable variations at 24 weeks for documented an infection (1.73 (1.50 to 1.96) further occasions per 1000 folks in these with a BNT162b2 first dose in contrast with mRNA-1273), covid-19 associated hospital admission (0.56 (0.45 to 0.67), and covid-19 associated loss of life (0.03, −0.00 to 0.07).12 Accounting for the longer follow-up interval and statistical uncertainty, these estimates are in keeping with our findings for the comparative effectiveness of mRNA-1273 versus BNT162b2 boosting.

A examine utilizing English information to estimate the effectiveness of BNT162b2 boosting versus no boosting and mRNA-1273 boosting versus no boosting individually utilizing a check negative-control design suggests marginally increased effectiveness towards symptomatic illness for mRNA-1273 than BNT162b2, however this assumes that the respective management populations in every evaluation have been comparable.13

The proof subsequently strongly factors to a good thing about mRNA-1273 over BNT162b2 for main vaccination and subsequent booster doses. That is related to vaccine procurement choices for future booster programmes. Nonetheless, each vaccines are protected and strongly efficient towards an infection and covid-19, in contrast with no boosting.913141516171819 Findings from this examine mustn’t discourage folks from receiving BNT162b2 booster vaccination if supplied.

Conclusions

Covid-19-related outcomes after vaccination with BNT162b2 or mRNA-1273 as a 3rd dose have been uncommon, though dangers have been estimated to be increased for BNT162b2 than for mRNA-1273. These findings have been broadly constant throughout subgroups. These represent vital variations at a inhabitants stage, however both vaccine is preferable in contrast with no booster dose.