Implications of obesity for drug administration and absorption from subcutaneous and intramuscular injections: A primer.

PURPOSE: To discuss the potential implications of obesity for drug administration and absorption from subcutaneous (SC) and intramuscular (IM) injection sites. SUMMARY: The SC and IM routes are useful for the parenteral administration of medications to optimize pharmacokinetic properties such as time to onset and duration of effect, for cost considerations, or for ease of administration, such as when intravenous access is unavailable. The choice of SC or IM injection depends on the specific medication, with SC administration preferred for products such as insulin where a slower and more sustained response is desirable, while IM administration is usually preferred for products such as vaccines where more rapid absorption leads to a more rapid antibody response. Obesity has the potential to influence the rate and extent of absorption, as well as adverse effects, of medications administered by the SC or IM route through changes in SC tissue composition and depth or by inadvertent administration of IM medications into SC tissue because of improper needle length. Potential adverse effects associated with IM or SC injections in addition to pain, bruising, and hematoma formation include sciatic nerve injury, particularly with IM injection in the upper outer quadrant of the buttock; bone contusion or rarely osteonecrosis if the IM injection is excessively deep; and granulomas, fat necrosis, and calcification with SC injection. CONCLUSION: Issues related to medication absorption in obese patients are likely to become more prominent in the future with increasing approvals of a wide range of biotherapeutic agents administered by SC injection. Studies should be directed toward these and other agents to assist with dosing decisions in this challenging population.

Homologous and Heterologous Covid-19 Booster Vaccinations.

BACKGROUND: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 µg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 µg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis.

Importance: Adverse events (AEs) after placebo treatment are common in randomized clinical drug trials. Systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide especially because concern about AEs is reported to be a reason for vaccination hesitancy. Objective: To compare the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials with those reported in the vaccine groups. Data Sources: For this systematic review and meta-analysis, the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched systematically using medical subheading terms and free-text keywords for trials of COVID-19 vaccines published up to July 14, 2021. Study Selection: Randomized clinical trials of COVID-19 vaccines that investigated adults aged 16 years or older were selected if they assessed solicited AEs within 7 days of injection, included an inert placebo arm, and provided AE reports for both the vaccine and placebo groups separately. Full texts were reviewed for eligibility by 2 independent reviewers. Data Extraction and Synthesis: Data extraction and quality assessment were performed independently by 2 reviewers, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and using the Cochrane risk-of-bias tool. Meta-analyses were based on random-effects models. Main Outcomes and Measures: The primary outcomes were the proportions of placebo recipients reporting overall, systemic, and local (injection-site) AEs as well as logarithmic odds ratios (ORs) to evaluate group differences. Outcomes were tested for significance using z tests with 95% CIs. Results: Twelve articles with AE reports for 45 380 participants (22 578 placebo recipients and 22 802 vaccine recipients) were analyzed. After the first dose, 35.2% (95% CI, 26.7%-43.7%) of placebo recipients experienced systemic AEs, with headache (19.3%; 95% CI, 13.6%-25.1%) and fatigue (16.7%; 95% CI, 9.8%-23.6%) being most common. After the second dose, 31.8% (95% CI, 28.7%-35.0%) of placebo recipients reported systemic AEs. The ratio between placebo and vaccine arms showed that nocebo responses accounted for 76.0% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose. Significantly more vaccine recipients reported AEs, but the group difference for systemic AEs was small after the first dose (OR, -0.47; 95% CI, -0.54 to -0.40; P < .001; standardized mean difference, -0.26; 95% CI, -0.30 to -0.22) and large after the second dose (OR, -1.36; 95% CI, -1.86 to -0.86; P < .001; standardized mean difference, -0.75; 95% CI, -1.03 to -0.47). Conclusions and Relevance: In this systematic review and meta-analysis, significantly more AEs were reported in vaccine groups compared with placebo groups, but the rates of reported AEs in the placebo arms were still substantial. Public vaccination programs should consider these high rates of AEs in placebo arms.

Efficacy, Immunogenicity and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis.

There is a significant research gap in meta-analysis on the efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines. This study analyzed the efficacy of COVID-19 vaccines. Published phase I, phase II, and phase III trials analyzing safety and immunogenicity and phase III randomized clinical trials evaluating the efficacy of COVID-19 vaccines were included. We searched MEDLINE, Scopus, and The Lancet for published articles evaluating the relative reduction in COVID-19 risk after vaccination. Selected literatures were published between December 15, 2019 and May 15, 2021 on the safety, efficacy, and immunogenicity of COVID-19 vaccines. This meta-analysis included studies that confirmed cases of COVID-19 using reverse transcriptase polymerase chain reaction. This study detected 8,926 eligible research articles published on COVID-19 vaccines. Of these, 25 studies fulfilled the inclusion criteria. Among the selected articles, 19 randomized clinical trials, 2 non-randomized clinical trials, and 3 observational studies were analyzed. Seven (28%) studies were included in the meta-analysis. The efficacy of the adenovirus vector vaccine was 73% (95% CI = 69-77) and that of the messenger RNA (mRNA) vaccine was 85% (95% CI = 82-88) in participants aged ≥18 years. There are no reports of clinical trials in participants aged under 16 years. The production of neutralizing antibodies against receptor-binding domains (RBDs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in >90% of the vaccinated samples was reported within 0-30 days of the first or the second dose of the vaccine. Pain at the injection site was the most common local symptom in people receiving mRNA vaccines (29%-85% of participants). Fever (0.2%-95%) was the most prevalent in people receiving adenovirus vector vaccines, and fatigue (8.4%-55%) was the most common side effect in people receiving the mRNA vaccines. Studies suggest that mRNA vaccines and adenovirus vector vaccines can provide moderate to high protection against COVID-19 infection in people over 18 years. Evidence of the long-term protection of the vaccines in people aged under 16 years against the multiple variants of COVID-19 are limited. This study will provide an integrated evaluation on the efficacy, safety, and immunogenicity of the COVID-19 vaccines.

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-µg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).

Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents.

BACKGROUND: Until very recently, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had not been authorized for emergency use in persons younger than 16 years of age. Safe, effective vaccines are needed to protect this population, facilitate in-person learning and socialization, and contribute to herd immunity. METHODS: In this ongoing multinational, placebo-controlled, observer-blinded trial, we randomly assigned participants in a 1:1 ratio to receive two injections, 21 days apart, of 30 µg of BNT162b2 or placebo. Noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants was an immunogenicity objective. Safety (reactogenicity and adverse events) and efficacy against confirmed coronavirus disease 2019 (Covid-19; onset, ≥7 days after dose 2) in the 12-to-15-year-old cohort were assessed. RESULTS: Overall, 2260 adolescents 12 to 15 years of age received injections; 1131 received BNT162b2, and 1129 received placebo. As has been found in other age groups, BNT162b2 had a favorable safety and side-effect profile, with mainly transient mild-to-moderate reactogenicity (predominantly injection-site pain [in 79 to 86% of participants], fatigue [in 60 to 66%], and headache [in 55 to 65%]); there were no vaccine-related serious adverse events and few overall severe adverse events. The geometric mean ratio of SARS-CoV-2 50% neutralizing titers after dose 2 in 12-to-15-year-old participants relative to 16-to-25-year-old participants was 1.76 (95% confidence interval [CI], 1.47 to 2.10), which met the noninferiority criterion of a lower boundary of the two-sided 95% confidence interval greater than 0.67 and indicated a greater response in the 12-to-15-year-old cohort. Among participants without evidence of previous SARS-CoV-2 infection, no Covid-19 cases with an onset of 7 or more days after dose 2 were noted among BNT162b2 recipients, and 16 cases occurred among placebo recipients. The observed vaccine efficacy was 100% (95% CI, 75.3 to 100). CONCLUSIONS: The BNT162b2 vaccine in 12-to-15-year-old recipients had a favorable safety profile, produced a greater immune response than in young adults, and was highly effective against Covid-19. (Funded by BioNTech and Pfizer; C4591001 ClinicalTrials.gov number, NCT04368728.).

Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021.

Monitoring adverse reactions following immunisation is essential, particularly for new vaccines such as those against COVID-19. We describe 20 cases of acute onset of a single supraclavicular lymphadenopathy manifesting between 24 h and 9 days after ipsilateral intramuscular administration of an mRNA-based COVID-19 vaccine, referred to our WHO Collaborating Centre for Vaccine Safety. Our results indicate that the swelling of supraclavicular lymph nodes following immunisation may constitute a benign and self-limited condition, related to a higher than recommended injection site.

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (Covid-19), have spread to millions of persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162b1 in younger adults have been reported previously from trials in Germany and the United States. METHODS: In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial conducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two lipid nanoparticle-formulated, nucleoside-modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor-binding domain; or BNT162b2, which encodes a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 µg, 20 µg, 30 µg, and 100 µg). In all groups but one, participants received two doses, with a 21-day interval between doses; in one group (100 µg of BNT162b1), participants received one dose. RESULTS: A total of 195 participants underwent randomization. In each of 13 groups of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2-neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. CONCLUSIONS: The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2-3 safety and efficacy evaluation. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).