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Our take —

There is a possible increased risk of developing Bell’s palsy in COVID-19 mRNA vaccine recipients, but the rate was extremely low (7 cases in 40,000 participants vaccinated), and was not statistically significantly different than the rate seen in the placebo recipients. This condition usually self-resolves. Preventing the risk of COVID-19 infection with vaccination greatly outweighs the incredibly small and less severe risk of Bell’s palsy, but this finding signals a potential issue that should be monitored in vaccine recipients moving forward.

Study design

Randomized Controlled Trial

Study population and setting

This analysis combined the safety results from publicly available data from the Pfizer-BioNTech and Moderna vaccine trials, which when combined have over 40,000 vaccine arm recipients. Bell’s palsy events, a condition that causes a temporary weakness or paralysis of the muscles in the face resulting in drooping or stiffening of one side of the face which usually self-resolves, were collected over a median of 2 months post vaccination.

Summary of Main Findings

7 cases of Bell’s palsy were detected in the vaccine recipients compared to 1 in placebo recipients, which translated to an incidence of 104 per 100,000 person-years in vaccinees and 15 per 100,000 person-years in placebo recipients, i.e., an estimated possible 7-fold higher rate in vaccinees, but this difference was not statistically significant. The incidence of Bell’s palsy in the general population is estimated to be between 15 to 30 cases per 100 000 person-years, indicating the rate of Bell’s palsy in the placebo arm was as expected, but the rate in vaccinees was potentially higher than expected.

Study Strengths

This report combines data from two large placebo-controlled clinical trials in which participants were carefully followed after immunization, so it is unlikely that events were missed, and the likelihood of misclassifying the event was low. Individually, and even combined, the trials did not have adequate sample size to rule out that the possibility that the higher rate in vaccinees was due to chance. However, the findings for both the Pfizer and the Moderna mRNA COVID vaccines, as well as a review of the risk of Bell’s palsy for other vaccines, namely influenza and meningococcal vaccines, which found excess risk in vaccinees in 5 of 6 studies examined, providing added support for their finding.

Limitations

No details on the duration and recovery status were provided nor was there a description of the characteristics of participants who experienced the event.

Value added

This re-analysis combined rare safety event data from two high-quality COVID vaccine trials to provide a more robust picture of the risk of Bell’s palsy. It also contextualized the findings with respect to risk observed with other vaccines and the background rate in the general population.

Our take —

This study was available as a preprint and thus was not yet peer reviewed. In-depth characterization of vaccine-induced adaptive immune response is a critical step in developing our understanding of COVID-19 immunity. A very thorough evaluation of both the humoral and cellular immune responses elicited by the Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine is presented here and provides largely encouraging data. However, the authors’ cursory assessment of the vaccine’s efficacy against the SARS-CoV-2 variants provides little reassurance, and should be largely disregarded. Although no evidence suggests that this vaccine’s efficacy would be reduced against any SARS-CoV-2 variant, the data presented here are insufficient to speak meaningfully to this topic.

Study design

Non-Randomized Trial

Study population and setting

This report presents data from a non-randomized open-label phase 1/2 trial evaluating humoral and cellular immune responses elicited in humans from the Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine, which encodes the entirety of SARS-CoV-2 spike (S) protein. The total study population consisted of 48 white individuals (21 male, 27 female) aged 19-55 years, and each participant received two doses of the vaccine 21 days apart in a prime-boost regimen, with each dose containing 1, 10, 20, or 30 ug mRNA (NB: the approved Pfizer/BioNTech vaccine product currently in use utilizes a 30 ug dose of mRNA for each dose). Total SARS-CoV-2 specific antibody levels, neutralizing antibody titers, and cellular immune responses were measured at various timepoints. Additionally, sera from vaccinated participants were evaluated for neutralization of pseudotype vesicular stomatitis virus (VSV) expressing S from different SARS-CoV-2 variants. Participants were monitored for adverse reactions.

Summary of Main Findings

Increases in total SARS-CoV-2 specific antibody levels were observed following both the first and second doses of the vaccine, with particularly robust responses noted following the boost. All doses above 10 ug elicited a similar response, and levels two months post-boost amongst these doses exceeded those observed in convalescent COVID-19 patients. Neutralizing antibody titers increased substantially only following the boost, with a strong dose-dependent response observed for the 10, 20, and 30 ug doses (the 1 ug dose did not elicit an appreciable neutralizing antibody response). Two months following boost, neutralizing antibody titers amongst vaccinated participants also remained elevated above titers observed in convalescent COVID-19 patients. Neutralizing titers against the SARS-CoV-2 variants assessed using the pseudotype VSV assay were similar to those observed against the reference virus used, which was obtained from a COVID-19 patient in Washington state in January 2020 (SARS-CoV-2 USA_WA1/2020).

Measurable CD4+ and CD8+ T-cell responses were elicited against multiple epitopes throughout S (i.e., not just within the receptor binding domain) in 32/34 and 34/37 participants analyzed, respectively, and were not clearly dose-dependent above 10 ug. Specific epitopes recognized by vaccine-induced T-cells were also identified. A TH1-predominant response was reported and reduces concern regarding the possibility of vaccine-induced disease enhancement. Finally, the strength of the cellular immune response was noted to correlate with the strength of humoral immune response within individuals. Consistent with previous reports, no serious adverse reactions were recorded.

Study Strengths

This study provides an in-depth analysis (much of which is beyond the scope of this summary) of the adaptive immune response elicited by a COVID-19 vaccine currently in wide use. Particular attention is given to characterizing T-cell responses, providing data that will likely prove valuable for numerous ongoing and future studies. Additionally, SARS-CoV-2 specific antibody levels and neutralizing antibody titers are evaluated out to approximately 2 months (63 days) post-boost, extending our current scope of knowledge.

Limitations

A narrow demographic was utilized for this study, and did not include any elderly or non-white participants. The variant neutralization assay appears to be an afterthought and that aspect of the study is poorly designed. Evidently, the variants utilized each differed from the reference receptor binding domain sequence within S only by a single amino acid, and thus are not at all representative of the variants that are currently of concern in circulation (e.g., B.1.1.7, B.1.351, P.1), which generally harbor mutations at numerous sites within S. Additionally, it seems that there was approximately a log-fold increase in neutralization titers when using the pseudotype VSV assay. Furthermore, as the correlate(s) of protection remain unknown at this time, measurement of only neutralizing antibodies at a single time point for the variant analysis provides extremely limited information regarding overall vaccine efficacy in this context.

Value added

This study provides one of the most in-depth characterizations of COVID-19 vaccine-induced adaptive immune responses to date.

Our take —

The Ad5 vaccine used in this study was well tolerated by participants in the first 28 days post-vaccination, and was able to induce the production of high levels of binding and low levels of neutralizing antibodies against SARS-CoV-2. While this initial trial had many limitations, it also showed promising results and therefore warrants further investigation, including long-term follow-up with the phase I trial participants and a larger scale phase 2 trial.

Phase 2 Results

This vaccine advanced to a Phase 2 Trial. A review and summary of it can be found here.

Study design

Non-Randomized Trial

Study population and setting

This was a Phase I, interventional trial run by CanSino Biologics Inc., taking place at Tongji Hospital in China. The vaccine being tested was an adenovirus type 5 (Ad5) vector engineered to express the Spike (S) gene of SARS-CoV-2. The enrollment period was March 16 to March 27, 2020. 108 healthy participants between 18 to 60 years were recruited and divided into three dose groups. The low-dose group received one dose of 5×1010 viral particles (vp) of recombinant novel coronavirus vaccine (Ad5-nCoV). The middle-dose group received one dose of 1×1011 vp, and the high-dose group received one dose of 1.5×1011 vp. Safety and tolerability of the vaccine were assessed for 28 days post-vaccination. The researchers also examined immunological responses to the vaccine at days 14 and 28 post-vaccination.

Summary of Main Findings

Some minor adverse events occurred within the first seven days post-vaccination, including pain at injection site, fever, fatigue, headache, and muscle pain; no serious adverse events occurred within the first 28 days. Participants with high pre-existing Ad5 immunity, which is the backbone of the vaccine, had a lower rate of fever post-vaccination. However, higher pre-existing Ad5 neutralizing antibodies were also associated with less seroconversion of SARS-CoV-2 neutralizing antibodies post-vaccination, as well as less CD4+ and CD8+ T cell responses against SARS-CoV-2. All three vaccine arms induced high titers of binding antibodies as measured by ELISA. Neutralizing antibody responses specific to SARS-CoV-2 increased in all three arms by day 14 from a baseline of zero, and peaked by day 28 post-vaccination. The high dose vaccine had a significantly stronger binding and neutralizing antibody response, however the magnitude of the neutralizing response appeared to be very low.  The low and middle dose vaccines will continue to a phase II efficacy clinical trial based on their safety profiles.

Study Strengths

This was the first published report of results of a phase I clinical trial for a vaccine against SARS-CoV-2. The S-protein sequence vectored into the Ad5 genome was full length, which may make it more clinically relevant than if it were only the receptor binding domain (RBD), as is being used for some other early stage vaccines. The study also followed multiple metrics to assess immunogenicity of the vaccine, including neutralizing antibodies, specific T-cell responses, and cytokines.

Limitations

This study has not addressed the long-term effects of the Ad5 vaccine, and this is a major concern for health officials when choosing a vaccine against SARS-CoV-2 to use for the public. As a phase I trial, it also had a small cohort size and lacked a randomized control group. Finally, participants only included individuals up to 60 years of age, and since age has been identified as a risk factor for severe SARS-CoV-2 disease, further investigation in older populations is warranted. Lastly, the antibody and T cell responses were not compared to recovered COVID-19 patients, so it is unclear how the vaccine-generated responses compare to those seen in natural infection.

Value added

This study marks the first report of an Ad5 vectored COVID-19 vaccine in a human clinical trial.

Our take —

This study is the first reported prospective clinical study of HCQ among laboratory confirmed SARS-CoV-2 patients. The study was non-randomized and nearly a quarter of patients initially enrolled were not analyzed. The primary outcome, viral shedding, was inconsistently measured and defined, and levels of viral RNA differed between the groups at baseline. While viral shedding appeared lower in the intervention arm, confounding factors are present. The study did not formally assess clinical endpoints, and it is unclear whether there is any clinical benefit to the treatment.

Study design

Non-Randomized Trial

Study population and setting

This trial took place in March 2020. Inclusion criteria were : >12 years of age, PCR-confirmed SARS-CoV-2 infection; exclusion criteria were: known allergy to hydroxychloroquine, known contraindication to drug, pregnant or breast-feeding. Intervention patients were recruited from a single hospital in Marseille,France; control patients were recruited from same hospital and 3 other hospitals/facilities in Southern France. Participants were followed daily for 14 days. Intervention patients (n=26) received 600mg daily hydroxychloroquine (HCQ). Azithromycin was added to the treatment in 6 of the intervention arm cases. Control patients (n=16) consisted of those who refused treatment with HCQ or who did not meet inclusion criteria. Treatments, if any, were not disclosed for controls. . The primary outcome was viral RNA shedding defined as a PCR-positive nasopharyngeal swab at day 6 post inclusion. Daily PCRs were done.

Summary of Main Findings

6/26 patients in the intervention arm were lost to follow-up, including 3 individuals who were transferred to the ICU and 1 who died. The primary analysis was based on 20 individuals in the intervention arm and 16 in the control arm. 6 (17%) of the 36 participants included in the analysis were asymptomatic, 22 (61%) had upper respiratory tract symptoms, and 8 (22%) had lower respiratory tract symptoms. Mean age of intervention arm participants was 51 compared to 37 in the control arm. Intervention arm participants were more likely to have lower respiratory symptoms and be male compared to control arm participants. Participants who received HCQ + azithromycin had lower viral RNA loads at treatment initiation than the HCQ only and control groups. At day 6, there was no detectable viral shedding in individuals who received HCQ+azithromycin. Viral shedding was observed in 43% participants with HCQ only and 88% of control arm participants.

Study Strengths

First reported prospective clinical study on the effectiveness hydroxychloroquine in SARS-CoV-2 infected patients.

Limitations

There were numerous limitations to this unblinded, non-randomized clinical trial. These included limited description of co-morbidities and demographics of the study population, substantial difference in age and severity of disease at study entry between arms, missing data on the primary study outcome, no statistical adjustment for differences between study arms, and no assessment of clinical endpoints. Additionally, the primary endpoint (viral shedding/clearance) was not consistently defined across patients and not assessed at the same frequency between arms. Levels of viral RNA at baseline were also lower in the one of the treatment groups, and sites other than the primary site did not perform daily PCR testing. The total length of follow-up was 14 days but only data through day 6 are shown. There were 6 individuals in the intervention arm excluded from primary analysis, 4 of whom had known relevant clinical outcomes (ICU transfer or death). Overall, there was limited data on clinical course or survival.

Value added

This study highlights that further research is needed to evaluate the clinical efficacy HCQ prior to general use.

Our take —

This trial will provide insight into the safety and reactivity of an Ad5-nCoV vaccine for COVID-19. The study has three treatment arms receiving different doses of the experimental vaccine, as well as subjects receiving placebo, so it is well designed. Though this is a relatively small trial (n = 108), it is one of the first of its kind. The study also plans to assess the persistence of the immune response elicited by the vaccine, which will be helpful in assessing its long-term efficacy, which is one of the ultimate goals of creating a vaccine against the novel coronavirus.

Study design

Non-Randomized Trial

Study population and setting

This is a Phase I, interventional trial run by CanSino Biologics Inc., taking place at Tongji Hospital in China. It began on March 16th, 2020 and is no longer recruiting. This trial has an enrollment of 108 participants who meet the following criteria: negative for COVID-19, between 18 and 60 years of age, negative for HIV, and able to complete the study process in seclusion over the 6-month duration of the trial. Most other underlying health conditions are criteria for exclusion from this trial.

Subjects are divided into three study arms: a low-dose group, middle-dose, and high-dose group. The subjects in each group receive either experimental vaccine or placebo via intramuscular (IM) injection to the deltoid muscle. The low-dose group received one dose of 5e10 viral particles (vp) of recombinant novel coronavirus vaccine (Ad5-nCoV). The middle-dose group received one dose of 1e11 vp, and the high-dose group received one dose of 1.5e11 vp.

The primary outcome measure of this trial is to evaluate the safety indices of adverse reactions in the first 7 days post-vaccination, with secondary outcome measures including additional safety indices for longer term timepoints. The vaccine is comprised of an adenovirus type 5 vector engineered to express the S gene, which is a part of the novel coronavirus’s genome. Other objectives of this trial are to analyze the production of S protein-specific antibodies against the novel coronavirus in the serum via various laboratory techniques, as well as anti-Ad5 vector neutralizing antibody responses, at 14 days, 28 days, 3 months, and 6 months post-vaccination. This trial also aims to investigate various aspects of humoral and cellular immunity with regards to the vaccine. For humoral immunity, the study plans to analyze the relationship between the amount of S protein-specific antibodies against virus and the vaccine dose given, the persistence of these antibodies in the serum of subjects of the different groups, and the relationship between dose and how long it takes for S protein specific antibodies to appear in the plasma. In terms of cellular immunity, the trial will probe these same questions, but for adaptive immune cells such as T cells.

Summary of Main Findings

N/A, study is incomplete

Study Strengths

N/A, study is incomplete

Limitations

N/A, study is incomplete

Value added

This is one of the first studies to test an adenoviral vector vaccine to attempt to elicit an antibody response against the novel coronavirus S-protein.

Our take —

This trial will evaluate the safety of a 2-dose vaccination schedule of mRNA-1273 for COVID-19. The study has three treatment groups, with 15 healthy adults in each group (total of 45 study subjects). Each treatment group will receive two vaccinations, spaced 28 days apart, but the dose of the vaccine will be different in each of the three groups. No placebo group was included, which is a limitation. The study will follow up with participants regularly to determine if they have any side effects, and will also investigate the immune response elicited by the vaccine 57 days after the second dose.

Study design

Non-Randomized Trial

Study population and setting

This is a phase I, open-label, dose ranging clinical trial in males and non-pregnant females, 18 to 55 years of age, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of mRNA-1273 manufactured by ModernaTX, Inc. mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike (S) protein of SARS-CoV-2. Enrollment has begun at sites in Georgia and Washington and started enrolling patients on March 3, 2020.

Fifteen subjects will be included in each of three escalating dosage groups: 25 microgram [mcg], 100 mcg, and 250 mcg. Subjects will receive an intramuscular (IM) injection (0.5 milliliter [mL]) of mRNA-1273 on Days 1 and 29 in the deltoid muscle and will be followed through 12 months post second vaccination (Day 394). Follow-up visits will occur 1, 2 and 4 weeks post each vaccination (Days 8, 15, 29, 36, 43, and 57), as well as 3, 6- and 12-months post second vaccination (Days 119, 209 and 394).

Summary of Main Findings

N/A, study is incomplete

Study Strengths

N/A, study is incomplete

Limitations

N/A, study is incomplete

Value added

This study will help in assessing the safety of the mRNA vaccine and also measure the seroconversion in individuals in a dose dependent manner.