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Our take —

This was a successful phase 1 trial with few adverse events and robust immune responses, comparable to or even stronger than those of recovered COVID-19 patients. The NVX-CoV2723 recombinant nanoparticle vaccine by Novavax warrants further investigation in a phase 2 trial due to these promising results.

Preprint review

This expert summary page was originally written on August 21, 2020 to assess the preprint report of the NVX-CoV2723 vaccine candidate. The preprint report was later peer-reviewed and published in the NEJM, as linked above. We reviewed the updated article on September 14 and determined that it remained very similar to the preprint. Therefore, our assessment below remains up-to-date.

Study design

Randomized Controlled Trial

Study population and setting

This phase 1/2 trial took place in Melbourne, Australia and examined the safety and immunogenicity of the NVX-CoV2373 vaccine developed by Novavax. NVX-CoV2723 is a recombinant nanoparticle vaccine comprised of the SARS-CoV-2 spike protein, which binds to the human ACE2 receptor. 134 healthy males and females between the ages of 18 and 59 were randomized into five groups to test 5 and 25ug doses of the vaccine with and without Matrix-M1 saponin-based adjuvant. Participants received vaccine doses on day 0 and day 21 in alternating deltoids, and data collection ended on day 35 for analysis.

Summary of Main Findings

Reactogenicity to the vaccine was mild, and it was generally well-tolerated by most participants. The use of the M1 adjuvant increased reactogenicity, but symptoms reported were generally ≤ grade 1. Adverse events usually lasted for ≤ 2 days. Strong anti-spike IgG antibody responses were detected by day 21, and even more so by day 28 (after the second vaccination). Neutralizing antibodies followed a similar trend, with the adjuvant vaccine showing a strong correlation between neutralizing antibody titers and anti-spike IgG. Following the second vaccination, these levels exceeded those found in convalescent serum from patients hospitalized due to SARS-CoV-2. Finally, antigen specific CD4+ T-cells were generated and produced inflammatory cytokines upon spike protein stimulation.

Study Strengths

This study has several strengths, including the fact that it is an alternative vaccine strategy compared to other COVID-19 vaccine candidate front-runners. Multiple dose groups were employed, and the use of adjuvant showed promising results for dose-sparing and vaccine efficacy. Antibody titers as well as T-cell responses were measured in this trial, and metrics were comparable to those from convalescent serum from patients requiring medical care for SARS-CoV-2.

Limitations

This trial only focused on a short observation time for safety and immunogenicity data, but such is the nature of phase 1 trial design. The population studied in this trial had no Black participants, and few non-white participants in general. Therefore, this particular trial did not encompass some of the most vulnerable and hard-hit groups in the COVID-19 pandemic.

Value added

First results from phase 1/2 trial of the NVX-CoV2373 recombinant nanoparticle vaccine.

Our take —

In this open-label randomized controlled trial, 5 days of Remdesivir was associated with a higher odds of a better clinical status compared to those receiving standard care among hospitalized patients with moderate COVID-19 disease severity. Because of multiple study limitations, the clinical significance of this finding is unclear.

Study design

Randomized Controlled Trial

Study population and setting

584 patients at 105 hospitals in the United States, Europe, and Asia, hospitalized with moderate COVID-19 (defined as pulmonary infiltrates and room-air oxygen saturation >94%). Patients were randomized open-label 5 day course of Remdesivir, a 10 day course, or standard of care. The median age was 57 years (IQR 46-66) and 227 participants (39%) were women. 56% had cardiovascular disease, 42% had hypertension, and 40% had diabetes. Patients were enrolled if they had a positive SARS-CoV-2 PCR test within 4 days of randomization. The median duration of symptoms before day 1 in the standard care group was 9 days (IQR, 6-11 days) compared with 8 days (IQR, 5-11 days) for both groups receiving remdesivir. The primary endpoint was Day 11 clinical status based on a 7-point ordinal scale; category 1 was death, category 7 was discharged.

Summary of Main Findings

533 (91%) of the participants completed the study through day 28. 76% of the patients 5 day remdesivir group completed the assigned treatment duration, as opposed to 38% of the 10 day group. The median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group (mostly due to discharge prior to completing 10 days of therapy). On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; P = .02). The clinical status distribution on day 11 between the 10-day Remdesivir and standard care groups was not significantly different (p= .18 by Wilcoxon rank sum test). There were a total of 7 deaths across the 3 groups and no difference in all-cause mortality by group at any of the assessed time points.

Study Strengths

Randomized controlled trial with a geographically diverse population.

Limitations

The study utilized open-label design, which could have led to selection bias. No virologic data was collected, and a significant number of patients did not complete their assigned treatment duration, primarily due to hospital discharge; this occurred more frequently in the 10 day group, and could have affected the results. A related limitation is that the 10 day group actually received a median of 6 days of remdesivir; thus this is not an effective comparison of 5 versus 10 days of treatment. The median duration of symptoms prior to randomization over a week in all groups. This could have affected the study results, as earlier administration of Remdesivir may be more efficacious than later administration. Lastly, other therapies used for SARS-CoV-2 as part of local standard of care were initially allowed. A major limitation was that the participants had moderate disease with low risk of mortality or clinical progression. It is unclear whether differences in outcomes would be observed by duration of remdesivir treatment with a sicker population.

Value added

This is the first randomized controlled trial of the use of Remdesivir in patients with moderate COVID-19.

Our take —

Inactivated virus vaccines have historically demonstrated safety and efficacy for use against other viral infections, and this approach continues to be promising and viable for use against COVID-19. The preliminary results here suggest the Sinopharm vaccine is safe and induces a robust antibody response. Completion of these trials, together with data from phase 3 trials, will provide crucial additional information regarding long-term safety, efficacy, and durability.

Study design

Randomized Controlled Trial

Study population and setting

This study presents an interim analysis of the safety and immunogenicity findings from two ongoing clinical trials (a phase 1 and a phase 2) in Henan Province, China evaluating the Sinopharm COVID-19 vaccine, which consists of β-propiolactone inactivated SARS-CoV-2 with an alum adjuvant. In the phase 1 trial, 96 participants were randomized and equally distributed to three vaccine dose groups (low, medium, high; with injections on days 0, 28, and 56) or an alum-only control group. In the phase 2 trial, 112 participants were randomized to two vaccine dose schedules (injections on days 0 and 14 ,or on days 0 and 28) using the medium dose from the phase 1 trial, with alum-only controls in a 1:3 ratio with vaccine recipients for each group.

For both trials, safety was assessed by recording adverse reactions for seven days following injection, and immunogenicity was assessed by measuring neutralizing antibody and total specific IgG titers 14 days after the final injection.

Summary of Main Findings

For both trials, adverse reactions were mild, with pain at the injection site as the most common finding, followed by transient fever; none required treatment. The overall incidence rate for adverse reactions was relatively low at 15%, possibly suggesting a superior safety profile compared to other COVID-19 vaccines currently in clinical trials.

Seroconversion rates were generally very high (most groups were 100%, with the lowest at 87.5%) for both neutralizing antibodies and total specific IgG. Booster injections given after a longer interval (21 or 28 days vs. 14 days) following the prime injection produced higher neutralizing antibody and total specific IgG titers.

Evidence from these clinical trials, and from preclinical studies in rhesus macaques, suggests that this inactivated vaccine is not associated with antibody-dependent enhancement (ADE) or vaccine-associated enhanced respiratory disease (VAERD), although further study is required to more definitively address these important safety concerns.

Study Strengths

The studies are well-designed double-blind, placebo-controlled, randomized clinical trials assessing both different doses and dose schedules for safety and immunogenicity. This combined interim analysis of both phase 1 and 2 trials together provides useful data that have been utilized to aid the design of phase 3 trials with this vaccine, which are now underway.

Limitations

This study is an unplanned interim analysis of ongoing clinical trials, and the authors stress that cautious interpretation is warranted as thorough analysis of the full dataset, when available, will be crucial for validation of these preliminary findings.

Although emerging evidence suggests neutralizing antibodies play an important role in immunity against SARS-CoV-2, the correlates of protection for COVID-19 remain poorly defined to date, and this study reports only humoral immune response data. Furthermore, methods for quantifying antibodies against SARS-CoV-2 are not yet broadly standardized, thus comparison between studies is difficult.

No possible explanation was provided for the greater seroconversion rate for neutralizing antibodies (41/42 participants) vs. total specific IgG (36/42 participants) for the 0- and 14-day group in the phase 2 trial.

Value added

This is the first clinical trial data reported for an inactivated SARS-CoV-2 vaccine against COVID-19.

Our take —

This Phase 1/2, placebo controlled study provides encouraging preliminary evidence that the COVID-19 RNA vaccine candidate (BNT162b1) is well tolerated and elicits an immune response at least comparable to antibody levels observed in a panel of convalescent plasma. This study suggests that a 10ug – 30ug dose of this vaccine candidate could be effective. This is a Phase 1 study, and as such is done with limited participant numbers. Larger Phase 2 and Phase 3 trials are still required to fully evaluate the efficacy of this vaccine candidate. Additionally, continued monitoring of participants will be done to evaluate safety and immune response over time.

Preprint Review

This expert summary is for the peer-reviewed article linked above. We also summarized this paper before it underwent peer-review.  You can find the original review of the preprint by clicking here.

Study design

Randomized Controlled Trial

Study population and setting

Phase 1/2 placebo-controlled, observer-blind study to determine the best dose of vaccine candi-date BNT162b1 based on safety, tolerability, immunogenicity and potential efficacy. This study is ongoing. Data from 45 participants is presented. Participants were mostly white (82.2.%) non-Hispanic/non-Latino (93.3%) healthy males (51.1%) and non-pregnant females (48.9%) age 18-55 years. Twelve participants received either a 10ug or 30ug vaccine dose on day 1 and 21. An additional twelve participants received a single dose of 100ug of vaccine.

Summary of Main Findings

The safety and tolerability profile of this vaccines is similar to that seen with other RNA-based vaccines, including pain at the injection site, mild to moderate fatigue, headache, and fever. Based on the reactogenicity of the first dose of 100ug, a second dose was not administered. Adverse events were reported by 50% of participants in the 10ug and 30ug dose group and by 58.3% of participants in the 100ug group. No severe adverse advents were reported. Serum antibody titers in all groups were significantly higher than those seen in a panel of COVID-19 convalescent human sera by 21 days post-first vaccination. Neutralizing antibody titers in all groups were 1.8 to 2.8-fold higher than a panel of COVID-19 convalescent human sera. Following the second dose, serum antibody titers specific to the receptor binding domains of SARS-CoV-2 spike protein were 8.0 to 50 fold higher than those found in a convalescent serum panel, and neutralizing antibody titers were 1.9 to 4.6 fold higher. This study suggests that a 10ug – 30ug dose of this vaccine candidate could be effective.

Study Strengths

This study was placebo controlled and monitored appropriate markers for safety and tolerability. Comparison of antibody titers to convalescent serum is helpful for understanding the magnitude of the immune response elicited by the vaccine candidate.

Limitations

There is no known correlate of protection for SARS-CoV-2 infection. While comparisons to convalescent plasma are informative, it is still unknown what types and magnitude of immune response is required for protection against SARS-CoV-2 infection. Continued monitoring of participants is ongoing and will be necessary to understand the safety and durability of the immune response beyond 2 weeks post-vaccination. This trial only included participants as old as 55 years of age. As older populations are at higher risk, the results from safety and immunogenicity studies in populations 55 and older will be required and are on-going. Additionally, this is part of a larger phase 1 trial including a total of 4 different vaccine candidates, but results from only one candidate trial are reported here. This study is ongoing.

Value added

This study provides encouraging preliminary evidence that the COVID-19 RNA vaccine candidate (BNT162b1) is well tolerated and elicits an immune response at least comparable to antibody levels observed in a panel of convalescent plasma.

Our take —

In this study, available as a preprint and thus not yet peer reviewed, COVID-19 vaccines utilizing inactivated whole SARS-CoV-2 continue to show promise in clinical trial data reported to date, with good safety profiles and acceptable immunogenicity. The vaccine evaluated here – Sinovac’s CoronaVac – likely compares favorably with the virtually identical offering from Sinopharm, although the several limitations noted above hinder more definitive conclusions at this time.Substantial revision will likely be present in any peer-reviewed version of this article, so the evaluation here should be taken with caution. Furthermore, the phase 3 trials currently either planned or underway with this vaccine in Bangladesh, Brazil, and Indonesia should yield crucial additional information.

Study design

Randomized Controlled Trial

Study population and setting

This study reports the findings from a phase 2 clinical trial evaluating the safety and immunogenicity of Sinovac’s CoronaVac COVID-19 vaccine, which consists of β-propiolactone inactivated whole SARS-CoV-2 with an aluminum hydroxide adjuvant. The trial was double-blinded, placebo-controlled, and involved 600 adults (ages 18-59) in Suining County, Jiangsu Province, China. Two doses (3 μg/mL or 6 μg/mL) were utilized in two schedules (injections on days 0 and 14, or days 0 and 28) in a ratio of 2:2:1 between the two vaccinated groups and the placebo group. Safety was assessed by self-reported adverse reactions, and immunogenicity was assessed by measuring total specific IgG against the receptor binding domain (RBD) and by measuring the neutralizing antibody (NAb) response.

Summary of Main Findings

Vaccination with CoronaVac was generally safe, with no serious adverse reactions reported, and immunogenic, with high NAb seroconversion rates (> 90%).

Study Strengths

The study design is generally acceptable and the data indicate that, similarly to the inactivated vaccine in development by Sinopharm, Sinovac’s CoronaVac may have a superior profile to many other vaccine platforms currently in clinical trials.

Limitations

This study has numerous limitations. The safety assessment consisted of only self-reported adverse reactions; blood samples for laboratory analysis were not obtained, and no data were provided regarding some of the specific safety concerns with COVID-19 vaccination (e.g. antibody-dependent enhancement). Immunogenicity was assessed only in terms of humoral response, and the data are not presented clearly (e.g. seroconversion rates are only generically said to be ‘over 90%’). Additionally, the total IgG assay used only the RBD as the antigen, the NAb assay used (a ‘modified cytopathogenic effect’) differs from those employed by most other COVID-19 vaccine studies to date (which use plaque reduction neutralization tests) which makes cross-study comparisons difficult. Also the explanations provided for the improved immunogenicity seen with vaccine formula used in the phase 2 trial versus that used in phase 1 (i.e. a greater amount of spike protein per virion), are questionable and insufficient data are presented for this assessment.

Regarding the phase 1 trial, references to ‘detailed information’ and a ‘coordinated submission’ of the phase 1 results are made, but we are unaware of any information available on the phase 1 results beyond Sinovac press reports and the phase 1 data confusingly scattered throughout this manuscript. Finally, numerous typographical errors (including grammatical/spelling mistakes and formatting irregularities), as well as a generally poor overall structure render this article difficult to read and reduce confidence in the data reported.

Value added

This study is the second to report clinical trial results assessing inactivated SARS-CoV-2 as a vaccine for COVID-19, and lends tentative additional support for this approach.

Our take —

This Phase 1, comparator-vaccine controlled study provides encouraging preliminary evidence that the ChAdOx1 nCoV-19 vaccine candidate is well tolerated and elicits an immune response at least comparable to antibody levels observed in a panel of convalescent plasma. This study suggests that a single dose of this vaccine candidate could be effective, but more data is needed regarding a prime-boost regime. This is a Phase 1 study, and as such is done with limited participant numbers. Larger Phase 2 and Phase 3 trials are still required to fully evaluate the efficacy of this vaccine candidate. Additionally, continued monitoring of participants will be done to evaluate safety and immune response over time.

Study design

Randomized Controlled Trial

Study population and setting

Phase 1/2 single blinded, comparator-vaccine controlled, randomized control trial performed in the UK to test the safety and immunogenicity of the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein. Healthy adults (1077 enrolled) age 18–55 years received a single dose of the virus or comparator control. A group of ten participants were assigned to a non-randomized, unblinded prime-boost group receiving the booster dose at 28 days after the initial dose.

Summary of Main Findings

No serious adverse events were reported. Systemic and adverse events (including pain, feeling feverish, chills, muscle ache, headache, and malaise) were more common in the CHAdOx1 nCoV-19 group, and were mostly mild or moderate and all self-limiting. Antibody responses to the spike protein were maximal at day 28 in the single dose group and increased by day 35 in the 2-dose group. Observed serum antibody levels were similar to those in a panel of convalescent serum. Neutralizing antibody responses against SARS-CoV-2 were also detected in the single and 2-dose groups.

Study Strengths

This study was controlled with a comparator vaccine and monitored appropriate markers for safety and tolerability. Comparison of antibody titers to levels in convalescent serum is helpful for understanding the magnitude of the immune response elicited by the vaccine candidate.

Limitations

There is no known correlate of protection for SARS-CoV-2 infection. While comparisons to convalescent plasma are informative, it is still unknown what types and magnitude of immune response is required for protection against SARS-CoV-2 infection. No data regarding T-cell response is reported here. Continued monitoring of participants will be necessary and is ongoing to understand the safety and durability of the immune response. This trial only included participants as old as 55 years of age, and the study population was not ethnically diverse. The results from safety and immunogenicity studies in more diverse populations and in populations 55 years and older will be required and are on-going. Additionally, the prime-boost group was very small and will need to be expanded to understand any possible benefit of a prime-boost regimen.

Value added

This study provides encouraging preliminary evidence that the ChAdOx1 nCoV-19 vaccine candidate is well tolerated and elicits an immune response at least comparable to antibody levels observed in a panel of convalescent plasma.

Our take —

The Ad-5 vectored COVID-19 vaccine tested in this phase 2 clinical trial exhibited promising results, inducing antibodies specific to the SARS-CoV-2 RBD, neutralizing antibody responses, and T-cell responses. Although, the researchers did not compare these results to convalescent plasma from recovered patients. The 5×10^10 viral particle vaccine dose proved to have an acceptable safety profile, and comparable immunogenicity to the higher dose studied in this trial. Therefore, this dose will be further analyzed in a larger phase 3 effectiveness trial in healthy adults.

Phase 1 Results

A review and summary of the Phase 1 trial for this vaccine can be found here.

Study design

Randomized Controlled Trial

Study population and setting

This study was a phase 2 clinical trial including 508 healthy adults from Wuhan, China age 18 and older. Low (5×10^10 viral particles) and medium (1×10^11 viral particles) doses from the phase 1 trial were selected for the study, as well as a placebo group, and randomized in a 2:1:1 fashion, respectively. Blood samples were collected on days 0, 14, and 28. Samples were tested for immunogenicity and patients were monitored to determine vaccine safety profiles.

Summary of Main Findings

Both vaccine doses resulted in SARS-CoV-2 RBD specific antibody responses by day 14, with even higher titers by day 28. Both doses also resulted in neutralizing antibody responses to live virus, as well as IFN-gamma T-cell responses. Participants age 55 years and older had a less immunogenic response to the vaccine, and many of them also had higher pre-existing adenoviral immunity. Both age and pre-existing Ad5 immunity could partially hamper immune response to the vaccine, and therefore these groups might be better suited for a booster dose of vaccine. This will be further explored in a phase 2b trial. The most common adverse events reported were fatigue, fever, and headache, as well as pain at injection site. Overall, the 5×10^10 viral particle dose group had a better safety profile with a comparable immune response to the 1×10^11 viral particle dose group.

Study Strengths

This was the first phase 2 trial for the non-replicating Ad5-vectored COVID-19 vaccine. This vaccine trial included a placebo group, and it had a wide range of ages in the participant pool, including a considerable percentage (13%) age 55 and older. This allowed them to analyze differences in vaccine response in the vulnerable older population. The vaccine did show promising results by inducing seroconversion and neutralizing antibodies, as well as positive T-cell responses.

Limitations

One limitation of this trial was that they began the phase 2 trial before the complete results of the phase 1 trial were available, therefore making the investigators unable to perform power calculations for this trial based on their previous results. This also caused them to make assumptions as to which vaccine dose would perform best, assigning more participants to that group, which turned out to be inaccurate. Next, all participants were from Wuhan, China, and no children were included in the study. Pre-existing Ad5 immunity is highly prevalent in the global population, and therefore there will likely be a large amount of pre-existing immunogenicity to the vaccine construct, which could dampen its effectiveness. Data was also only collected up to 28 days post-vaccination, and therefore long-lasting immunity is still in question. Additionally, the correlates of protection against SARS-CoV-2 are still unknown. Finally, the researchers did not compare their results to those found in convalescent plasma, which has been used in other studies as a comparison group.

Value added

First report of results from the Ad5-vectored COVID-19 vaccine phase 2 trial, with promising findings warranting proceeding to phase 3 trials.

Our take —

The mRNA-1273 COVID-19 vaccine from Moderna shows promise as it has been proven overall safe in phase 1 clinical trials, as well as immunogenic. The medium dose of 100ug elicited high neutralization responses, as well as Th1 CD4 T-cell responses, and is moving on to a phase 2 trial. True correlates of protection against SARS-CoV-2 have not yet been determined, so it is difficult to say for certain whether this vaccine will provide protection in the long term. Participants from this trial will be followed for one year, so we are not yet able to comment on the resilience of the immune response elicited from the vaccine.

Study design

Randomized Controlled Trial

Study population and setting

This study was a phase 1 clinical trial including 45 healthy adults between the ages of 18 and 55 years old divided evenly into three groups receiving low, medium, and high doses of Moderna’s mRNA-1273 vaccine in two injections 28 days apart. This analysis includes results through follow-up on day 57.

Summary of Main Findings

Following the first vaccination, antibody responses increased in a dose dependent fashion, with seroconversion in all participants by day 15. Antibody titers increased dose-dependently again after the second dose vaccination. Neutralizing antibodies were detected in all participants after the second dose via two methods. This supports the need for a two-dose vaccination schedule. Neutralizing antibodies in trial participants reached similar levels to those in convalescent serum samples. The most common adverse events included fatigue, chills, headache, myalgia, and pain at injection site, with a greater incidence following the second vaccine dose. All 15 participants in the medium dose group and 14/15 in the high dose group reported solicited systemic adverse events following the second dose. The highest number of overall adverse events was in the high dose group, and 3/15 in this group reported severe adverse events, including fever.

Study Strengths

This study was an example of deployment of a vaccine for human clinical trials in record time, taking only two months to accomplish a task that normally takes years to complete. The safety profile of this vaccine is similar to that of other previously published Moderna influenza mRNA vaccines. The mRNA-1273 vaccine proved to be immunogenic in all participants, with all showing binding and neutralizing antibody responses. These responses were similar to antibody levels detected in convalescent serum specimens.

Limitations

This trial included a small number of participants, which is consistent with phase 1 study design. However, 89% of participants were white. More diversity is needed in the phase 2 cohort, especially since SARS-CoV-2 has disproportionately affected minority populations in the US. Additionally, most patients were around 30 years of age, while the older population is a group that needs the most protection from the virus. There were a few instances of severe adverse events reported in the high dose group. Additionally, no detection of a T-cell response was mentioned for the high dose group.

Value added

First report of results from the mRNA-1273 vaccine’s phase 1 trial, with promising findings warranting proceeding to phase 2 trials.

Our take —

This report of a Phase 1 vaccine study was available as a preprint and was thus not yet peer reviewed. This was a randomized, placebo-controlled study that provided encouraging preliminary evidence that the COVID-19 RNA vaccine candidate (BNT162b1) is well tolerated and elicits an immune response at least comparable to antibody levels observed in a panel of convalescent plasma. This study suggests that a 10ug – 30ug dose of this vaccine candidate could be effective. Participant numbers were limited. Larger Phase 2 and Phase 3 trials are still required to fully evaluate the efficacy of this vaccine candidate. Additionally, continued monitoring of participants will be done to evaluate safety and immune response over time.

Updated Review Available

This expert summary is for the non peer-reviewed preprint. We also summarized this paper after it underwent peer-review and was published in Nature on August 11, 2020. You can find our updated review of the published article here.

Study design

Randomized Controlled Trial

Study population and setting

Phase 1/2 placebo-controlled, observer-blind study to determine the best dose of vaccine candidate BNT162b1 based on safety, tolerability, immunogenicity and potential efficacy. Among 45 participants enrolled and randomized, most were white (82.2.%) or non-Hispanic/non-Latino (93.3%), healthy males (51.1%) or non-pregnant females (48.9%) aged 18-55 years. Twelve participants received either a 10ug or 30ug vaccine dose on days 1 and 21. An additional twelve participants received a single dose of 100ug of vaccine, and 9 received the placebo.

Summary of Main Findings

The safety and tolerability profile of this vaccines is similar to that seen with other RNA-based vaccines, including pain at the injection site, mild to moderate fatigue, headache, and fever. Based on the reactogenicity of the first dose of 100ug, a second dose was not administered. Adverse events were reported by 50% of people in the 10ug and 30ug dose group, and by 58.3% of participants in the 100ug group. No severe adverse advents were reported. Serum antibody titers in all groups were significantly higher than those seen in a panel of COVID-19 convalescent human sera by 21 days post vaccination. Neutralizing antibody titers in all groups were 1.8-2.8-fold higher than those in a panel of COVID-19 convalescent human sera. This study suggests that a 10ug – 30ug dose of this vaccine candidate could be effective.

Study Strengths

This study was placebo controlled, participants were randomized to the different treatment arms and monitored for appropriate markers for safety and tolerability. Comparison of antibody titers is helpful for understanding the magnitude of the immune response elicited by the vaccine candidate.

Limitations

There is no known correlate of protection for SARS-CoV-2 infection. While comparisons to convalescent plasma are informative, it is still unknown what types and magnitude of immune responses are required for protection against SARS-CoV-2 infection or disease. Continued monitoring of participants will be necessary and is ongoing to understand the safety and durability of the immune response beyond 2 weeks post-vaccination. This trial only included participants less than 55 years of age. As older populations are at higher risk, the results from safety and immunogenicity studies in populations 55 and older will be required and are on-going. Additionally, this is part of a larger Phase 1 trial including a total of four different vaccine candidates, but results from only one candidate trial are reported here.

Value added

This study provides encouraging preliminary evidence that the COVID-19 RNA vaccine candidate (BNT162b1) is well tolerated and elicits an immune response at least comparable to antibody levels observed in a panel of convalescent plasma.

Our take —

This randomized controlled trial demonstrated that dexamethasone was associated with decreased overall mortality in hospitalized patients receiving supplemental oxygen and mechanical ventilation. Treatment was also associated with decreased mortality in patients who experienced symptoms for at least seven days but not those with more recent onset. Treatment did not result in mortality reductions for patients with milder disease presentations who did not require supplemental oxygen. This study did not examine whether the benefit from dexamethasone could be expanded to other sub-groups or if dexamethasone conferred harm to people who did not have oxygen requirements. Furthermore, this was a short-term study that did not measure long-term sequelae of dexamethasone use, such as increased risk of fungal infections.

Study design

Randomized Controlled Trial

Study population and setting

This paper, which was posted as a preprint and had not yet been peer-reviewed, reported on 6,425 patients admitted to 176 National Health Service hospitals in the UK with either suspected or laboratory confirmed SARS-CoV-2 between March 19 and June 8, 2020. Exclusion criteria included medical history that might place a patient at “significant risk” in the opinion of the attending clinician. Initially, patients were required to be at least 18 years of age, but this criterion was later dropped. Of the participating patents, 2104 were randomly allocated to receive dexamethasone (six mg/day for up to 10 days) plus standard of care and compared to 4321 patients who received standard of care alone. The primary end point was death from any cause (i.e., all-cause mortality) within 28 days of randomization. Patients who were discharged alive, but not followed for the full 28 days to assess for death because the study had ended, were assumed to have survived for 28 days.

Summary of Main Findings

Dexamethasone reduced overall all-cause mortality by 17% (Risk ratio (RR) = 0.83, 95% CI: 0.75-0.92), with the effect being greatest in patients who had most severe respiratory compromise. For example, dexamethasone decreased mortality by 35% in patients requiring intubation and mechanical ventilation and by 20% in patients requiring supplemental oxygen therapy. (RR=0.65, 95% CI: 0.51–0.82 and RR=0.80, 95% CI: 0.70–0.92, respectively). However, dexamethasone did not affect the mortality of patients not requiring respiratory support (RR=1.22, 95% CI: 0.93–1.61). Specific sub-groups that benefitted from dexamethasone were persons under the age of 70, men, and persons whose symptoms had been ongoing for more than seven days at the time of randomization. Another important concern is that persons who were moderately ill, and did not require oxygen at baseline, may have had slightly worse outcomes with dexamethasone, although this was not statistically significant.

Study Strengths

This study benefited from a large, multi-center, prospective randomized treatment population with a comparable control group. The primary outcome measurement was 28-day, all-cause mortality. The team only considered outcomes in people who had either died prior to 28 days or who had a full 28 days of follow-up, avoiding the censoring of data from people who had incomplete follow-up. Follow-up data was available for 95% of patients. A majority (82%) of patients were laboratory-confirmed for SARS-CoV-2, and they were well-balanced between the group that received dexamethasone and the comparator arm. Other investigational agents (e.g., lopinavir-ritonavir, hydroxychloroquine) were infrequently used and if they were used, well-balanced between the two arms.

Limitations

The manuscript had not yet been peer-reviewed at the time of our review. There was no breakdown by race or ethnicity, which may be a significant predictive risk for worse outcomes. Pre-existing hypertension and obesity, two major risk factors for COVID-19 severity, were also not reported. Clinician opinion on “high risk” as a contraindication to participation in the trial was vague and thus, the results may not be generalizable to populations at “high risk”, however that was defined. Similarly, patients on mechanical ventilation were 10 years younger than those not receiving respiratory support, which may indicate that patients who were more likely to survive were prioritized to receive ventilators; thus, this may limit generalizability of these results to populations requiring respiratory support but with low probabilities of survival. Furthermore, not all patients had RT-PCR confirmed SARS-CoV-2, which may limit the generalizability of these results to populations where the suspected cases outnumber laboratory-confirmed cases. It is also worth noting that this was an open-label study, where the researchers and patients in the study knew who was receiving which treatment. While a masked trial, where researchers and patients do not know who is receiving which treatment, are generally known to be less biased, it is difficult to see how the unmasked approach here would have biased mortality data. Lastly, the study protocol stated that patients randomized to receive dexamethasone could receive it for up to 10 days, and the breakdown in Table S1 shows that the duration of treatment with dexamethasone varied widely across patients [interquartile range: 3-10 days]. Thus, a subgroup analysis conducted on the duration of dexamethasone would be helpful.

Value added

This is the largest randomized controlled trial of a pharmaceutical intervention for COVID-19 to date. In addition, the mortality benefit from dexamethasone is the most substantial that has been seen in a therapeutic RCT for COVID-19. The number of mechanically ventilated patients who would need to be treated with dexamethasone is eight to save one life.