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Our take —

This was a double-blind randomized controlled trial from Argentina with 160 patients which showed that early, high-titer convalescent plasma given within 72 hours of COVID-19 symptom onset significantly reduces progression to severe respiratory disease over the subsequent 15 days.

Study design

Randomized Controlled Trial

Study population and setting

This was a double-blind randomized controlled trial of 160 elderly patients early in the course of COVID-19 disease, comparing convalescent plasma (CP) to placebo, conducted across 15 institutions in Argentina. Eligible individuals were either 75 years or older, or 65-74 years of age with at least one chronic coexisting condition with <48 hours of one sign and one symptom of COVID-19 and a positive SARS-CoV-2 PCR. All participants received either CP, with an IgG titer >1:1000 of anti-spike protein, or placebo infusion within 72 hours of symptom onset. The primary endpoint was progression to severe respiratory disease, defined as tachypnea (30 breaths per minute or greater) or hypoxemia (less than 93% oxygen saturation on room air) within 15 days following the infusion with either convalescent plasma (n=80) or placebo (n=80).

Summary of Main Findings

In the intention-to-treat analysis, 13 out of 80 (16%) participants in the CP arm compared to 25 out of 80 (31%) in the placebo arm reached the primary endpoint of severe respiratory disease, a significant reduction (RR 0.52, p 0.03). The combined secondary endpoint of life-threatening respiratory disease, critical systemic illness, and/or death occurred among 7 (9%) CP arm participants and 12 (15%) placebo arm participants (not statistically significant).

Study Strengths

The study assessed early use of CP, when it is most plausibly effective. In addition, all CP units were considered high-titer. Moreover, the selected population of patients aged 75 or greater, or 65-74 with one or more comorbidities, targets a specific population at high risk of COVID-19 morbidity and mortality.

Limitations

The study stopped recruiting participants prematurely because of a lowered incidence of COVID-19 cases in the regions of Argentina available to recruit from, which made it difficult to have enough statistical power to evaluate secondary outcomes, although they appear to be better in the CP group. The trial was not powered to assess the combined severe illness or death secondary outcome.

Value added

This study is a first from a placebo-controlled RCT to demonstrate that high-titer convalescent plasma, when given very early in the course of COVID-19, can reduce progression to severe respiratory disease among a high-risk population.

Our take —

These phase 3 clinical trial results demonstrate that the NIH-Moderna mRNA vaccine is safe, and is highly efficacious (94%) against COVID-19. They also reinforce the findings from the other Pfizer developed mRNA vaccine, which also generated >90% protection. In addition, this study provided interesting data on effectiveness of the vaccine after only one injection, however these findings should be assessed with caution and further study is needed to fully verify those results. Pressing questions remain unanswered at this time, however, and are centered on identifying the correlates of protection against COVID-19, as well as determining the vaccine’s durability, its ability to prevent asymptomatic SARS-CoV-2 infection, as well as any possible long-term safety concerns.

Study design

Randomized Controlled Trial

Study population and setting

This study evaluated the NIH-Moderna SARS-CoV-2 mRNA vaccine in a blinded, placebo-controlled phase 3 clinical trial. At 99 centers across the United States, 28,207 participants, aged 18 years and older without evidence for current or previous SARS-CoV-2 infection included in the per-protocol analysis in approximately a 1:1 ratio of vaccine to placebo recipients. The participants were stratified according to age (> 65 or < 65 years), as well as for risk of developing severe COVID-19 disease for those < 65 years only (determined by presence of preexisting conditions per CDC criteria). All analyzed participants received two injections of either 100 μg mRNA-1273 or placebo 28 days apart. The primary endpoint measured was the prevention of first-occurrence, symptomatic, PCR verified SARS-CoV-2 infection at least 14 days following the second injection.

Summary of Main Findings

196 subjects developed laboratory verified COVID-19, with 11 cases in the vaccine group (3.3 per 1,000 person-years) and 185 in the placebo group (56.5 per 1,000 person years), suggesting that a two-dose regimen of the NIH-Moderna SARS-CoV-2 mRNA vaccine is approximately 94.1% effective at preventing COVID-19. Some level of protection may be afforded following a single dose starting approximately 14-days after the first injection, although the study was not explicitly designed to evaluate this outcome. Consistent with previous trial phases, the vaccine was well-tolerated and side effects were minimal. Additionally, no evidence was found for enhancement of disease following infection in the vaccinated group (e.g., antibody-dependent enhancement or vaccine associated enhanced respiratory disease); on the contrary, the data suggest the vaccine may lessen the severity of COVID-19, as all of the severe cases were in the placebo group.

Study Strengths

The study group was sufficiently large and diverse in terms of age, race, and ethnicity. Numerous secondary end points (e.g., efficacy following a single dose, ability to prevent severe COVID-19, safety, etc.) were included.

Limitations

As this trial is still ongoing, not all data is available at this time. Data regarding prevention of asymptomatic infections are not reported here. However, these data were collected as per the clinical trial protocol and should be reported in the future. Additionally, increased transparency and data sharing (the current data sharing statement simply says that data ‘may’ be shared at the conclusion of the trial in 2022) are warranted for a study of this magnitude and gravity and would increase the confidence of both the scientific community and the public in the reported results.

Value added

The phase 3 trial data published here for one of the two currently authorized and available vaccines in the United States provides crucial and largely reassuring information for vaccine recipients.

Our take —

The best hope for overcoming COVID-19 epidemic is the development of efficient vaccines. This study, available as a preprint and thus not yet peer reviewed, showed that this whole inactivated SARS-CoV-2 virion vaccine (manufactured by Bharat Biotech) is safe and can induce significant immune responses against the virus. In addition, the data showed that this vaccine induces immune response against multiple viral components including the spike protein, the primary target for the vaccines currently approved for emergency use. However, a phase 3 clinical trial is needed to test the efficiency of this vaccine in preventing COVID-19.

Study design

Randomized Controlled Trial

Study population and setting

This is data from the phase 2 clinical trial for the SARS-CoV-2 vaccine BBV152, a whole inactivated virion formulated with an adjuvant to enhance the immune response (manufactured by Bharat Biotech). The study included 380 healthy volunteers between ages 12- 65 years recruited from 11 centers across India. The participants were screened for previous SARS-CoV-2 infection and were randomly assigned to receive one of two vaccine formulations at days 0 and 28. Side effects of the vaccine were monitored for one week after vaccination and immune response was assessed for four weeks after the second dose of the tested vaccine. The study also included the assessment of the vaccine immunogenicity in 198 participants who were included in the phase 1 clinical trial, along with their controls.

Summary of Main Findings

The study found that the vaccine induced minor side effects including fever, chills, aches, malaise and weakness in about 10% of the participant. No severe or life-threatening adverse reactions were reported. The vaccine induced antibodies that can bind to the SARS-CoV-2 virus in over 98% and 92% of the participants receiving the high and low doses, respectively. The authors showed also that the whole inactivated virion induced immune memory cells, suggesting possible longer-term protection of this experimental vaccine.

Study Strengths

The current study has the advantage of including a relatively large number of participants for a phase 2 clinical trial across many centers in India and simultaneously testing two different formulations. The study also included children and teens 12 years and older, compared to Pfizer and Moderna vaccines that are approved for adults above 16 and 18 years respectively. Most of the front runner vaccines focus on targeting SARS-CoV-2 spike protein. The current study tested a vaccine prepared from a whole inactivated virion and showed some evidence of inducing immune response toward the other viral proteins as well. However, it is not clear if targeting other viral proteins can provide any further protection against SARS-CoV-2 infection.

Limitations

This is a phase2 clinical trial so does not present any data on vaccine efficacy. In addition, the study was conducted solely in India and there is no data about ethnic backgrounds of the participants.

Value added

The study showed a whole inactivated virion vaccine against SARS-CoV-2 is safe and induces an immune response. While this is not the first inactivated vaccine that was tested, considering the wide spread of COVID-19 in the world and current vaccine shortage, any effective vaccine can help mitigate the consequences of this disease world-wide.

Our take —

This study, available as a preprint and thus not yet peer reviewed, includes both phase 1 and phase 2 clinical trial data demonstrating the safety and immunogenicity of ZF2001, a vaccine manufactured by Anhui Zhifei Longcom Biopharmaceutical. This is the first clinical data reported for an RBD-based protein subunit vaccine for COVID-19. The vaccine was well tolerated and immunogenic. The data strongly support continued studies in phase 3 trials. Phase 3 trials are ongoing with a 25 ug, 3-dose regimen.

Study design

Randomized Controlled Trial

Study population and setting

Reported are results from phase 1 and phase 2 clinical trials of a SARS-CoV-2 S protein receptor-binding domain (RBD)-based protein subunit vaccine against COVID-19, ZF2001, manufactured by Anhui Zhifei Longcom Biopharmaceutical. Both trials were randomized, double-blinded, and placebo-controlled. The phase 1 study enrolled 50 healthy adults, aged 18-59 into one of three groups: 25 ug vaccine, 50 ug vaccine, or placebo. All groups were administered 3 doses 30 days apart. The primary endpoint was safety, with the secondary endpoint of immunogenicity. Phase 2 studies enrolled 900 participants and included six groups, with three groups receiving 3 doses of either 25 ug vaccine, 50 ug vaccine, or placebo, and 3 groups receiving 2 doses of either 25 ug vaccine, 50 ug vaccine, or placebo. Primary endpoints were safety and immunogenicity. In both studies, samples were taken at determined intervals to assess immunogenicity. Both trials were conducted in China, with phase 1 in Chongqing and Beijing, and Phase 2 in Xiangtan.

Summary of Main Findings

All vaccine regimens were well tolerated. Local adverse events included pain, swelling, induration, redness, rash and pruritus. Systemic adverse events included fever, cough, dyspnea, diarrhea, anorexia, nausea, vomiting, muscle pain other than the injection site, arthritis, joint pain, headache, fatigue, acute allergic reaction, irritation or inhibition, and mental disorder. No vaccine-related serious adverse events were reported. In the phase 1 study, 61% (25 ug group) and 79% (50 ug group) of participants had seroconverted by day 30 post-first dose and 100% of both groups had seroconverted by day 30 post-second dose. In the phase 2 study, 59-65% seroconverted by day 30 post-first vaccination, 94%-97% at 30 days post-second vaccination, and 97%-99% at 14 days post-third dose. However, for all vaccine groups in both phase 1 and phase 2 studies, neutralizing titers were only similar to or better than convalescent patient serum at time points following the third dose. There was no significant enhancement of neutralizing titers in the 50 ug groups compared to the 25 ug groups. T-cell responses were also observed in all vaccine groups with no significant difference between groups. Maximal responses first observed at 30 days post-second dose.

Study Strengths

Demonstration of neutralizing antibodies titers elicited by this vaccine equal to or greater than convalescent plasma is positive. While a correlate of protection has not been determined for SARS-CoV-2, to date, vaccines that have been issued an emergency use authorization (EUA) have demonstrated neutralizing titers similar to or better than convalescent plasma.

Limitations

While demonstrating that ZF2001 can elicit a T-cell response is positive, it is not clear what type or level of response is needed to confer protection against disease. This study did not include elderly populations and has very limited population diversity. Also, duration of the immune response is not tested past 30 days post-third dose. These limitations will be addressed in the ongoing phase 3 trial. The data indicate that the immune response is greatly boosted with the 3rd vaccination, thus a 25 ug, 3-dose regimen will be used in the phase 3 trial. A 3-dose vaccine regime could prove to be logistically difficult in some areas and compliance may be lower than the current 2-dose regimens for other vaccines already in use under EUA.

Value added

This is the first clinical data reported for an RBD-based protein subunit vaccine for COVID-19. The vaccine was well tolerated and immunogenic. The data strongly support continued studies in phase 3 trials.

Our take —

This phase 1/2 study demonstrates that a Th1-biased immune response is elicited by a single dose of the ChAdOx1 vaccine (developed by Oxford & AstraZeneca). This is favorable because Th2-biased cytokine secretion has been shown to enhance disease for other coronaviruses, though this has not been demonstrated for SARS-CoV-2. The results here are encouraging, and this vaccine candidate has moved on to ongoing phase 2/3 trials in order to assess its efficacy. Additionally, this vaccine has received Emergency Use Authorization in the UK as well as several other countries, but not yet in the US.

Study design

Randomized Controlled Trial

Study population and setting

Information on study recruitment and participant demographics was previously reported in Folegatti et. al. 2020. Participants ranged from age 18 to 55 and were either given 5×1010 viral particles of the ChAdOx1 vaccine (manufactured by AstraZeneca) or control vaccine (MenACWY). On days 7, 14, 28, and 56 post-vaccination, blood samples were collected for analysis of the immune response.

Summary of Main Findings

Serum from study participants showed Th1-biased cytokine secretion in response stimulation with SARS-CoV-2 spike protein. B cell proliferation was increased at all post-vaccination time points. IgM and IgA antibodies specific to the spike protein were produced, in addition to IgG, which was previously reported. The IgG subclasses are mainly IgG1, found in about half of participants, and IgG3, found in almost all participants. Broad Th1-biased CD4+ and CD8+ T-cell responses specific to the S1 and S2 subunits of the SARS-CoV-2 spike protein were detected. Notably, immune response did not differ based on sex, or with age within this population.

Study Strengths

This study presented a full characterization of the immune response after one dose of the ChAdOx1 vaccine, examining a wide variety of immune system components. The results also included data on if there was a difference in the immune response based upon sex, which is important since COVID-19 seems to affect men more severely than women.

Limitations

The study included a relatively small cohort of participants who were mainly white, and also limited to age 18 to 55 years old. Additionally, little is known about the effectiveness of adenovirus-based viral vectors as vaccines compared to traditional vaccine types.

Value added

A detailed analysis of the immune response after a single dose of the ChAdOx1 vaccine.

Our take —

Less reactogenicity was experienced after the booster dose of ChAdOx1 vaccine (developed by Oxford & AstraZeneca) compared to the initial dose of the vaccine, independent of dose interval. This is the opposite of what has been found for other mRNA vaccines. The authors posit investigation of schedules mixing vaccine technologies to reduce overall instances of reactogenicity. Overall, the ChAdOx1 vaccine was well tolerated in a two-dose regimen. Multifunctional antibody responses and T-cell responses that were induced by the initial vaccine dose were enhanced by a booster dose. The two-dose regimen is currently being evaluated in phase 3 trials. Additionally, this vaccine has received Emergency Use Authorization in the UK as well as several other countries, but not yet in the US.

Study design

Randomized Controlled Trial

Study population and setting

Participants between the ages of 18 and 55 years were recruited between April 23 and May 21, 2020. 52 participants who had already received one dose of the ChAdOx1 vaccine were boosted with a second dose of vaccine 56 days later, with 10 receiving control MenACWY vaccine instead. A “dose-sparing” half dose was also tested on day 56. Data on participants receiving a booster dose 28 days after the initial dose was previously reported and was reproduced in this paper for comparison between booster strategies. Adverse events, anti-spike antibody titers, T-cell responses and cytokine production were analyzed.

Summary of Main Findings

The booster dose of the ChAdOx1 vaccine resulted in minimal side effects, less than the initial dose. This was consistent for all booster regimens, and no serious adverse events were reported. Neutralizing antibody titers increased after the initial dose, with an even further increase following the booster dose. However, a half dose booster resulted in lower antibody titers than the others. Antibody-dependent phagocytosis was induced by the initial dose and enhanced by booster doses, more so with 56d interval booster. Complement deposition also increased. Similar increases in anti-spike IgM, IgG, and IgA antibodies were achieved for all boost strategies. Anti-spike IgG levels were similar to that in convalescent plasma by day 14, though no correlate of protection has been identified so the relevance of these antibody levels is unclear. No significant increase in spike-specific T-cells was seen following any of the booster doses. The anti-vector immune response slightly increased following booster consistently across groups but did affect anti-spike immune response. No correlation between pre-existing anti-vector immunity and side effects after booster was found.

Study Strengths

This study compared results from their participants to serum samples from a cohort of 21 convalescent serum donors. They also tested multiple booster dosing schedules as well as doses, taking into consideration the possibility of dose-sparing.

Limitations

Participants were limited to ages 18 to 55 years, excluding vulnerable elderly populations. The cohort size for this study was also small. Finally, true correlates of protection against SARS-CoV-2 are still unknown.

Value added

A description of the immune response after different booster doses and schedules using the ChAdOx1 vaccine.

Our take —

This study details findings from the ACTT-2 trial, a double-blind, placebo-controlled, randomized controlled trial involving 1,033 patients hospitalized with COVID-19 in 8 countries. Addition of baricitinib to remdesivir was shown to be superior to remdesivir alone in time to recovery, improvement in clinical status, and adverse effects. While several short-term outcomes improved in the baricitinib arm, the ACTT-2 study was limited by lack of long-term follow-up and lack of treatment protocol standardization. In addition, the benefit of baricitinib was most evident among people with moderate illness at baseline, and did not appear beneficial for people with milder or more severe disease. Additional studies are needed to place baricitinib in the context of other anti-inflammatory drugs for treatment of COVID-19, especially with respect to dexamethasone and other corticosteroids that may also have proven mortality benefits for COVID-19.

Study design

Randomized Controlled Trial

Study population and setting

The ACTT-2 study involved 1,033 adults hospitalized with COVID-19 admitted to 67 hospitals in 8 countries between May 8 and July 1, 2020. At each hospital, patients were randomized in equal proportions to either combination therapy (remdesivir plus baricitinib) or control (remdesivir plus placebo). The dose of baricitinib was adjusted for glomerular filtration rate (GFR). Inclusion required a positive SARS-CoV-2 RT-PCR test, and evidence of lower respiratory tract infection based on radiographic infiltrates, SpO2 ≤94% on room air, or requirement of supplementation oxygen. Exclusion criteria were hepatic injury (ALT or AST levels at >5 times the upper limit of normal), renal injury (estimated GFR>30 mL/min/mm2), need for hemodialysis or hemofiltration, contra-indication to study drug, pregnancy or breast-feeding, or anticipated transfer elsewhere within 72 hours. The primary outcome was time to recovery during the 28 days after enrollment using the World Health Organization Ordinal Scale for Clinical Improvement, with recovery defined as the first day on which an individual achieved categories 1, 2, or 3 on the Ordinal Scale. A major secondary outcome was clinical status at 15 days post-enrollment.

Summary of Main Findings

In intention-to-treat analysis, addition of baricitinib to remdesivir therapy reduced median time to recovery from 8 days to 7 days (rate ratio 1.16, 95% CI: 1.01 to 1.32, p 0.03). Among participants who were category 6 on the Ordinal Scale at baseline (receiving non-invasive ventilation or high-flow oxygen), the median time to recovery was 10 days for baricitinib compared with 18 days for control (rate ratio 1.15, 95% CI: 1.10 to 2.08), but this difference was not significant in patients with either less or more severe disease. In secondary analysis, improvement in clinical status at day 15 was greater for the baricitinib arm (odds ratio 1.3, 95% CI: 1.0 to 1.6), and the highest benefit was observed for patients who were category 6 on the Ordinal Scale at baseline (odds ratio 2.2, 95% CI: 1.4 to 3.6). The incidence of progression to death or ventilation was lower in the baricitinib arm compared to control (22.5% vs. 28.4%, 95% CI: 0.60 to 0.98). The baricitinib arm also had fewer serious adverse effects (16.0% vs. 21.0%; p 0.03) and new infections (5.9% vs. 11.2%; p 0.003) compared to control. There was no significant difference in 28-day mortality between patients receiving baricitinib or placebo (5.1% vs. 7.8%; hazard ratio 0.65, 95% CI 0.39 to 1.09).

Study Strengths

This study assigned patients to combination therapy vs. control, with randomization stratified according to disease severity and trial site. The design was double-blind and placebo-controlled, meaning the participants and study teams were blinded to treatment, to minimize reporting bias. A diverse patient population was recruited from hospital sites across multiple countries, enhancing the generalizability of findings. In addition, a large proportion of Hispanic or Latino patients (51.4%) was enrolled in this study, an important strength given how disproportionately COVID-19 has affected these communities. Analyses were also stratified by sex, race, ethnic group, duration of symptoms before hospitalization, site location, and pre-existing conditions, allowing for detailed analysis of patient subgroups most amenable to baricitinib addition. Importantly, most sub-groups continued to show benefit of the addition of baricitinib, although not with statistical significance.

Limitations

While recruitment from multiple hospitals may enhance generalizability of results, this led to heterogeneity in standard of care protocol. For hospitals with a written policy for COVID-19 treatments, patients could receive these additional treatments in addition to the experimental intervention. The prevalence of these additional interventions in each group was not specified in the results, and consequently there were no adjustments for elements that constituted a given standard of care. Additionally, there was a high loss of patients to follow-up in both baricitinib and placebo arms (40 vs. 41), although this was balanced between the two arms of the study. It is worth noting that there was an imbalance of participants in the placebo arm with no other comorbidities compared to baricitinib arm (18.3% vs. 12.9%). Median time of symptom onset to enrollment was relatively long at 8 days for each arm, precluding analysis of the benefits of short-term administration of baricitinib. Since most patients with early COVID-19 are not admitted to the hospital, there is likely to be significant bias in enrolling patients at later stages of disease. While there were fewer short-term adverse effects in the baricitinib arm, follow-up for patients was ceased at 29 days, precluding analysis of long-term effects of drug treatment or all-cause mortality. Importantly, the combined outcome of mortality and use of ventilation was not pre-specified, so statistically significant results may have arisen by chance. Multiple secondary outcomes, including clinical status, use of oxygen, use of ventilation, mortality, adverse effects, and duration of hospitalization, were measured, and the analyses were not corrected for multiple comparisons. In addition, since dexamethasone has recently been shown to improve mortality of persons with COVID-19, it would have been important to adjust the risk models for co-administration of for all corticosteroids in general and for dexamethasone specifically.

Value added

This study provides valuable descriptive data on occupational groups most impacted by COVID-19 over the course of the pandemic.

Our take —

Data from this Phase 2/3 vaccine trial from 43,548 participants in the US, Argentina, Brazil, Turkey, South Africa, and Germany strongly support that Pfizer’s BNT162b2 is safe and highly efficacious with 95% protection against COVID-19. Data about how long immunity lasts and whether this vaccine prevents asymptomatic infections will be forthcoming.

Study design

Randomized Controlled Trial

Study population and setting

This was a Phase 2/3 placebo controlled, observer blinded study in healthy people aged 16 years and older. The mRNA-based vaccine (BNT162b2) or placebo was administered in 2 doses at least 21 days apart. Study participants were split 1:1 between the vaccine and placebo arms. A total of 43,548 participants were enrolled in the United States, Argentina, Brazil, Turkey, South Africa, and Germany. Participants were monitored for adverse events from the time of injection and for COVID-19 disease (reporting at least one symptom with a positive RNA test) from seven days after the second dose. This report does not include efficacy for asymptomatic infections since these data are still being analyzed.

Summary of Main Findings

This paper reported on interim safety and efficacy data from Phase 2/3 of an ongoing global Phase 1/2/3 trial. BNT162b2 is a lipid nanoparticle formulated, nucleoside-modified RNA (modRNA) vaccine encoding the SARS-CoV-2 Spike protein. This interim report indicates that the BNT162b2 vaccine is 95% efficacious. As of this report, 8 out of 21,720 participants in the vaccine arm and 162 out of 21,728 in the placebo arm had confirmed symptomatic cases of COVID-19. This level of efficacy was similar across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. However, the study was not powered to demonstrate statistical significance between these subgroups. After the first dose but before the second dose, 39 COVID-19 cases were observed in the BNT162b2 group and 82 cases in the placebo group indicating 52% efficacy after only a single dose of BNT162b2. Of 10 observed severe cases, 9 were in the placebo and 1 was in the vaccinated group. While these numbers are too low to draw definitive conclusions, the trends suggest the vaccine will also protect against severe cases of COVID-19. The safety profile of BNT162b2 (assessed for at least 2 months up to 14 weeks post second dose) was acceptable. Of the 43,252 participants in the study, serious adverse events were rare and similar in the vaccine and placebo groups (0.6% and 0.5%, respectively). Most common adverse reactions were mild-to-moderate pain, redness, swelling at the injection site, fatigue, and headache. Reported local reactions did not increase upon the second inoculation, however systemic reactogenicity (mostly fevers and headaches) did increase in both frequency and severity. While deaths occurred in both the vaccine (n=2) and placebo (n=4) groups, none of these deaths were attributable to vaccination or were due to COVID-19.

Study Strengths

This study far exceeded the predefined metrics for success (30% efficacy) to demonstrate that BNT162b2 is a safe and highly efficacious vaccine against COVID-19. Subgroups with multiple risk factors were included in this study (35% obese, 21% had at least one coexisting condition, 42% were over 55 years of age) suggesting that the vaccine will be effective in the most at risk individuals.

Limitations

This was an interim analysis of a Phase 2/3 clinical trial. As such, there are still outstanding data to be collected and analyzed. Data demonstrating the durability of the immune response and protection against asymptomatic infection remain to be analyzed. The study population here was also predominantly white (83%), therefore, more data in more diverse populations will be necessary to fully know if any differences in efficacy exist. As is typical in vaccine development, this study did not include children, pregnant women or immunocompromised individuals. Future studies in these populations are planned. The safety data reported here does not include 196 participants infected with HIV. These data were collected and will be analyzed separately, per the protocol.

Value added

This study demonstrated that the BNT162b2 vaccine is safe and efficacious against COVID-19. Importantly, it demonstrated that mRNA vaccines are a viable and promising approach as a new vaccine technology. Additionally, it showed the feasibility of the continuous phase 1/2/3 trial design, which could be beneficial for development of future vaccines.

Our take —

This combined interim analysis of four large-scale blinded randomized controlled trials including 11,636 participants shows that an adenovirus-based SARS-CoV-2 vaccine delivered in a prime-boost strategy is extremely safe, and can provide moderate (63% in full dose prime) to excellent (90% in low dose prime) protection against symptomatic COVID-19 disease, though the fact that the low dose prime strategy resulted from a vaccine production error and only involved a subgroup of participants in a single site complicates interpretation. Protection against asymptomatic infection was only observed in the low dose prime group, suggesting this strategy may be the most beneficial moving forward and warrants further investigation.

Study design

Randomized Controlled Trial

Study population and setting

This is an interim report of results from four vaccine trials that examined the safety and efficacy of the Oxford/Astra Zeneca SARS-CoV-2 vaccine. The vaccine is made up of a replication deficient adenovirus-based backbone that expresses SARS-CoV-2 Spike protein, and has shown good safety and immunogenicity in previous phase 1 and 2 studies. This paper describes the combined efficacy results of two dose strategies of the vaccine (two full doses of 5 x 105 vaccine particles, or one low dose followed by a second full dose; in both strategies doses are given at least 4 weeks apart) versus a placebo control (meningococcal vaccine or saline) in a 1:1 fashion from two of the three sites included in the larger phase 3 study, United Kingdom and Brazil. The low dose followed by a high dose strategy was not originally planned, but later adopted for one group of participants in the UK due to an error in vaccine production; this also led to variation in timing of the second dose in that group. The primary endpoint of the trial was virologically confirmed, symptomatic COVID-19 among patients with at least one of the following symptoms: measured fever, cough, shortness of breath, anosmia or ageusia. In addition, UK participants were asked to self-swab weekly to evaluate differences between groups in asymptomatic shedding. Safety data from these trials, as well as earlier phase 1 and phase 2 studies in the United Kingdom and South Africa were also analyzed. 11,636 people aged 18+ years were included in the interim efficacy analysis and were analyzed according to the treatment they received.

Summary of Main Findings

The participants that received both full doses of vaccine were 62% less likely to experience symptomatic COVID-19 infection at least 14 days after the second dose of the vaccine versus the placebo arm (27 of 4400 [0.6%] vs 71 of 4455 [1.6%] respectively). In this group receiving two full doses, vaccine efficacy was highly similar in both the UK and Brazil participants, even though the populations were different, with the UK group being slightly older and less racially diverse. In a smaller group, participants in the UK who received a low-dose of the vaccine followed by a full dose were 90% less likely to experience symptomatic RNA-confirmed COVID-19 (3 of 1367 [0.2%] vs 30 of 1374 [1.7%]). Among 126,324 identifiable swabs from UK participants, there was no observable protection from asymptomatic infection for the vaccinated participants who received both full doses of the vaccine, whereas the participants who received a low dose followed by the full dose were 58.9% percent less likely to have an asymptomatic infection. There were 10 cases of COVID-19 that resulted in hospitalization, which occurred 21 days or more after treatment (two were classified as severe cases of which one died). All of these cases were in the placebo arm. Lastly, using data from all participants who received at least one dose from all four phase 1, 2, and 3 trials (74,341 person-months of follow-up), the vaccine appeared extremely safe with a very low incidence of severe adverse events that were evenly split between the two arms (84 events in 12,021 participants in the vaccine arm and 91 in 11,724 participants in the control group), with only three events being classified as being possibly related to the vaccine or placebo.

Study Strengths

This is the first published assessment of the efficacy of a COVID-19 vaccine, and one of the primary strengths of the paper is the large amount of detail the researchers provided to explain their results. Another strength of the study is that the researchers assessed protection from asymptomatic infections and viral shedding, which is not being measured by all COVID-19 vaccine trials. In addition, by combining results from the UK, Brazil, and South Africa the study analyzes both safety and efficacy in diverse populations facing very different epidemics. Given this diversity in the study populations, the similarity in results between the UK and Brazil increases the overall confidence in the effectiveness of the vaccine. Lastly, the authors clearly state the role of the funders in the presentation of the results, and a detailed listing of any conflicts of interest.

Limitations

While the variability in the doses and the diversity of study sites and protocols combined in this report are a strength from a research point of view, it is also a limitation in the ability of the researchers to precisely determine the overall efficacy of the vaccine. While the authors reported that when combining all their data the vaccine is 70% effective, this number combines two different dosing strategies, used in different populations, and with varying timing between doses, and is therefore is somewhat problematic. Although, it should be noted that this strategy was discussed and approved by regulators prior to the analysis. The authors also report the results of the trial according to dosing strategy used, which is a more accurate way to present the data. In addition, due to an error in dosing the vaccine in early phase 1 and 2 studies, a portion of the participants in the UK cohort received an initial lower dose of the vaccine, which resulted in better protection for both symptomatic and asymptomatic infection. Those in this low dose cohort also received the second dose after a significant gap (<1% within 8 weeks of first dose). Additionally, although older participants (>55 years) were included later in the trial, the numbers are too small to make firm conclusions on vaccine effectiveness in this population. However, this research team has previously shown that the vaccine does induce a similar immune response in older individuals, suggesting similar efficacy would be expected in this population. Due to the nature of the pandemic, it is impossible to know the duration of protection beyond 6 months, but further analyses are planned to address this issue. Lastly, as this is an interim analysis, the efficacy results of the vaccine may change slightly as more follow-up data become available, though this is not expected to result in a significant change in efficacy.

Value added

This study provides the first detailed assessment of the safety and efficacy of an adenovirus-based SARS-CoV-2 Spike vaccine in multiple populations, and provides encouraging results that this vaccine can provide moderate to strong protection from symptomatic COVID-19.

Our take —

Oxford and AstraZeneca’s ChAdOx1 vaccine was safe and well-tolerated across all age groups in this trial of 560 participants, actually being better tolerated in older adults ages 56 and older. Similar levels of neutralizing antibody titers against SARS-CoV-2 were achieved across all age groups when using a prime-boost vaccine dosing strategy. This vaccine showed promising results in phase 2, and warranted further investigation in a larger scale, phase 3 trial, which was also recently published.

Study design

Randomized Controlled Trial

Study population and setting

This paper is focused on safety and efficacy results from the phase 2 portion of a phase 2/3 trial testing Oxford and AstraZeneca’s ChAdOx1 vaccine against SARS-CoV-2. The trial took place at 20 sites across the UK, with results from two sites highlighted here. The study took place between May 30 and August 8, 2020 and included 560 participants. Patients were divided into three age groups: 18-55, 56-69, and 70 years and older, with 400 of the participants considered older adults (ages 56+ years). The vaccine was given in a single or two dose regimen, 28 days apart. Participants were given either a low (2.2 x 1010 viral particles) or standard dose (3.5 – 6.5 x 1010 viral particles) of ChAdOx1 nCoV-19, or a placebo vaccine. Clinical and immunologic data was collected on days 0, 7, 14, and 28 after both prime and booster doses, if applicable.

Summary of Main Findings

This trial observed no serious adverse events related to the safety of the vaccine. Fatigue, headache and muscle pain were the most commonly reported systemic adverse events, as well as pain at injection site. However, reactogenicity to the inoculation decreased with increasing age. Immunogenicity was assessed by measuring levels of neutralizing antibodies and immune response after vaccination. There was an increase in receptor binding domain (a part of the viral spike protein) specific neutralizing antibodies one month after the booster dose, while there was no increase in antibodies specific to the adenoviral vaccine vector itself. Neutralizing antibody titers were observed at comparable levels across all age and dose groups by one-month post-booster vaccine. IFN-γ levels peaked following the prime dose, but did not increase significantly after the booster dose.

Study Strengths

This vaccine uses a simian adenovirus instead of one that normally infects humans in order to combat the issue of pre-existing immunity to the adenoviral vector. Two different doses, as well as two different dosing strategies, were studied here. Additionally, a wide age range of older adults were enrolled as participants. This is key because they are a critical population to be vaccinated since they are much more susceptible to severe cases of COVID-19.

Limitations

The participants enrolled in this trial were mainly white, and with few co-morbidities. Future studies will need to address more diverse populations. The low dose of the vaccine was produced by two separate manufacturers, and as a consequence two different injection volumes were used, which could have influenced local reactogenicity. Neutralizing antibodies are still being used as a correlate of protection here, but no true correlate of protection has yet been defined. Finally, the oldest participants averaged in the low 70s age range, and this may not be representative of those living in long-term care facilities and other older individuals who will need the vaccine.

Value added

Safety and immunogenicity results of Oxford and AstraZeneca’s phase 2 adenoviral vectored vaccine trial including a population of older adults.