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INTRODUCTION

As of the middle of November 2021, nearly 47 million cases of coronavirus disease 2019 (COVID-19), including more than 750,000 deaths, have been reported in the United States. Over the past few months, the delta variant (B.1.617.2) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the predominant strain in the United States, according to the U.S. Centers for Disease Control and Prevention (CDC). Nearly 99% of isolates currently being identified are delta variants. While the delta strain of SARS-CoV-2 continues to predominate, there is good news lately, as cases have plateaued and decreased significantly in a number of geographic areas.

In addition, continued widespread vaccination efforts by many health care providers — including pharmacists — have resulted in nearly 225 million adults receiving at least 1 dose of a COVID-19 vaccine, representing 68% of the U.S. population. More than 194 million people aged 12 years or older are fully vaccinated, representing 69% of those in this age group in the United States, and children aged 5–11 years are beginning to be vaccinated. Approximately 16 million adolescents between the ages of 12–17 have received at least 1 dose of COVID-19 vaccine (Pfizer/BioNTech), most occurring since the U.S. Food and Drug Administration (FDA) authorization in May 2021.

As the pandemic has continued for nearly 2 years, a number of reports have demonstrated waning of SARS-CoV-2 antibodies over time. This has led to FDA approvals of booster doses to be considered for various populations. In addition, the feasibility of people receiving different company’s vaccines, including adenovirus vaccine and mRNA vaccines, has been authorized as so-called “mix and match” regimens. And as mentioned above, the Pfizer/BioNTech COVID-19 vaccine was authorized in the young school age population in early November 2021.

Details regarding these primary hot topics within COVID-19 vaccination are discussed in this continuing education program. New developments in oral antiviral therapy for treatment of outpatient mild-to-moderate COVID-19 disease are also reviewed.

Rationale and Authorization for Booster COVID-19 Vaccines

As used to describe COVID-19 vaccinations, “fully vaccinated” refers to having received either 1 dose of the Johnson & Johnson/Janssen vaccine or 2 doses of either of the mRNA vaccines manufactured by Pfizer/BioNTech or Moderna. Participants in studies who have been fully vaccinated demonstrate significant protection against severe disease, manifested by hospitalization and/or death, compared with unvaccinated participants. However, because of a perfect storm — long duration of the pandemic, significant percentage of population who have yet to be vaccinated, and transmissibility of the delta strain — cases spiked significantly in many geographic regions of the United States. The spikes were particularly marked in regions with large proportions of unvaccinated people, but increased cases also occurred elsewhere, including in regions with higher vaccination rates.

A number of studies have begun to evaluate waning of antibodies, and unfortunately, they have demonstrated lower antibody levels and decreased vaccine effectiveness. A recently published study in Science evaluating more than 750,000 U.S. veterans looked at vaccine effectiveness based on vaccine types and the vaccines’ protection against infections. Over a 9-month period from February 2021 to October 2021, overall vaccine effectiveness decreased from 87.9% to 48.1%. The adenovirus vaccine (Johnson & Johnson/Janssen) showed the largest drop in vaccine effectiveness, declining to 13.1% at the end of the evaluation period. However, vaccine effectiveness with respect to infections also declined significantly for the Pfizer/BioNTech and Moderna vaccines, decreasing at the end of the evaluation period to 43.3% and 58%, respectively.¹

Protection against death from COVID-19 declined but remained relatively higher. From July to October, vaccine effectiveness with respect to mortality in people younger than 65 years of age was 81.7% for any vaccine, 73.0% for Johnson & Johnson/Janssen, 81.5% for Moderna, and 84.3% for Pfizer/BioNTech. For people 65 years of age or older, vaccine effectiveness with respect to death dropped to 71.6% for any vaccine, 52.2% for Johnson & Johnson/Janssen, 75.5% for Moderna, and 70.1% for Pfizer/BioNTech. While vaccination provided significant benefit versus both infection and mortality over time, a decrease in effectiveness was observed over this time period during which the delta strain was predominant.¹

The question then becomes does providing booster doses to certain populations of fully vaccinated patients decrease the risk of infection and severe disease including death? A large study published in Lancet specific to the Pfizer/BioNTech vaccine helps to answer this question. Using data from Clalit Health Services in the Israeli population, participants who received a BNT162b2 booster dose (following full vaccination with 2 primary doses) were matched 1:1 to similar controls who had not received the booster dose. Each group contained 728,321 participants who were eligible for the study only if they were fully vaccinated at least 5 months before the recruitment date, had no previous COVID-19 infection, and had no health system exposure within 72 hours of enrollment. Vaccine effectiveness was 93% with the booster dose (95% CI, 88%–97%), compared with the 2-dose primary series. A booster dose was also significantly more effective in preventing severe disease (admission to hospital) and death compared with the 2-dose group, with rates of 92% and 81%, respectively. Death rates were overall low in both groups, with 44 deaths occurring in the 2-dose group and 7 in the booster group.²

Based on these data and several other studies involving all 3 authorized vaccines, FDA has now authorized booster doses for an expanded number of patient populations. The authorizations differ slightly among the available vaccines, as follows:

• Moderna — A single booster dose may be given at 6 or more months after full vaccination (2 injections) to people who are aged 65 years or older, 18–64 years of age and at high risk of severe COVID-19, or with frequent institutional or occupational exposure to SARS-CoV-2. It is important to note that the booster dose of the Moderna vaccine is 0.25 mL, which differs from the 0.5-mL primary vaccination doses.
• Pfizer/BioNTech —Initially approved as a booster dose for older adults in September 2021, BNT162b2 may also be given as a booster dose 6 months or more after full vaccination to individuals 18–64 years of age who have frequent exposure to SARS-CoV-2 through health care institutions (e.g., hospital, nursing home) or occupation (e.g., nurse, community pharmacist).
• Johnson & Johnson/Janssen — A single booster dose may be given at least 2 months after completion of the single dose initially administered to adults aged 18 years of age or older.

Both the Moderna and Pfizer/BioNTech vaccines were previously authorized by the FDA for boosters to be an option for people with certain immunocompromised conditions, which has not changed. No boosters are currently authorized for any person younger than 18 years of age.

Mixing and Matching of COVID-19 Vaccine Boosters

Questions have arisen with regard to “mixing and matching” of the 3 currently authorized COVID-19 vaccines in the United States. Clinically, the question is whether mixing different vaccine boosters (even using 2 different mRNA vaccines) would provide greater immunogenicity compared with providing consistent boosters with the same vaccine used in the primary COVID-19 vaccine therapy.

A recently published study (preprint not yet peer reviewed) has given some insight into this question. In a phase 1/2 open-label trial conducted at 10 sites in the United States, 458 adults who had been vaccinated with 1 of the 3 currently authorized COVID-19 vaccines at least 12 weeks earlier received 1 of the 3 vaccines as a booster dose. Participants had not been infected with SARS-CoV-2 previously. It should be noted that the Moderna booster dose given in this study was 0.5 mL, not the 0.25-mL booster that is currently authorized by the FDA. The primary outcomes were safety, reactogenicity, and humoral immunogenicity at days 15 and 29.

For the booster doses, 154 participants received Moderna vaccine, 150 received Johnson & Johnson/Janssen vaccine, and 153 received the Pfizer/BioNTech vaccine. Reactogenicity developed at rates similar to those in the primary injection series. More than 50% of participants experienced injection site pain, malaise, headache, and muscle pain. No serious adverse events were reported related to study vaccination. Regarding antibody responses, all groups demonstrated an increase in binding antibodies following a booster dose, with a 2-fold or greater rise in 96%–100% of participants. The mean rise in binding antibodies ranged from 4-fold to 56-fold increase at day 15 and were greatest in the group initially receiving the Johnson & Johnson/Janssen vaccine followed by either the Pfizer vaccine (33-fold increase) or Moderna vaccine (56-fold increase). The smallest increase occurred in patients receiving the Johnson & Johnson/Janssen vaccine as the booster, resulting in a 7-fold to 10-fold lower increase compared with those receiving mRNA vaccines for the booster dose. In general, baseline binding antibody concentrations and post-boost binding antibody concentrations were lower compared with the pseudotyped lentivirus strains that presented the SARS-CoV-2 spike protein. Serum neutralizing antibody concentrations were about 3- and 10-fold lower for the Pfizer and Johnson & Johnson/Janssen recipients compared with Moderna recipients, regardless of interval between initial vaccinations or booster vaccination.³

Based on these data along with other studies, the FDA has now approved mixing and matching of booster COVID-19 vaccines among all 3 authorized agents. The populations for whom these booster doses are authorized are similar to those populations listed above for which the agents are approved as long as the time intervals are maintained. It appears that patients who were vaccinated with the single-dose Johnson & Johnson/Janssen product may benefit more from a boosted dose with either mRNA vaccine as opposed to a second injection with the same adenovirus vaccine. These approved authorizations for heterologous booster injections will provide one less logistical step for those patients who are being vaccinated at various pharmacies as they can receive whichever product is available or use a different preferred vaccine. More long-term data will be needed on immunogenicity of these heterologous regimens and also outcomes such as cases, severe cases with hospitalizations, and deaths caused by COVID-19.

Vaccination of Children Ages 5–11

In the United States, there continues to be vaccine hesitancy among a significant number of adults, despite valiant efforts by pharmacists and other health care providers to provide education regarding overall COVID-19 vaccine efficacy and safety, with more than 428 million vaccine doses administered in the United States. To date, children ages 5–11 years have accounted for 39% of cases in patients younger than 18 years of age and 8,300 hospitalizations and 146 deaths. Based on historical estimates, this would qualify as the 8th leading cause of death among this age group. Documentation of safety and efficacy in children becomes more important to provide maximal protection against COVID-19, including severe illness and death.

In the data submitted by Pfizer to the FDA, 1,518 participants aged 5–11 years receiving BNT162b2 were compared with 750 patients receiving placebo for vaccine efficacy and safety. Patients had not had COVID-19 before enrollment in the study. Participants receiving active vaccine were given 10-mcg doses (reduced from 30 mcg in adults and adolescents) in 2 separate injections 3 weeks apart. An expanded safety analysis included an additional participants who received BNT162b2 and 788 participants who received placebo to provide a more robust analysis of serious adverse effects and other adverse effects of interest, such as myocarditis. Vaccine efficacy against symptomatic COVID-19 (after 7 days after full vaccination) was 90.7% in the BNT162b2 group (2-sided CI, 67.4%–98.3%). The raw numbers of symptomatic cases of COVID-19 were 3 and 16 in the treatment and placebo groups, respectively. None of these cases was categorized as severe.

The most commonly reported solicited adverse reactions in this trial included injection site pain (71%), fatigue (39.4%), and headache (28%). The most common unsolicited adverse reaction was lymphadenopathy (0.9%). In the combined 3,109 patients who received BNT162b2, 4 serious adverse reactions occurred, none of which was attributed to study vaccine. There were no cases of myocarditis, pericarditis, or anaphylaxis and no deaths reported. Subgroup safety analysis of a number of characteristics did not demonstrate any notable differences compared with the overall population studied, acknowledging that that some subgroups had small number of participants. While most of the initial 1,518 patients were followed for 2 months after the vaccine was administered, the second safety group was followed for about 2.4 weeks after the vaccine was administered. Safety surveillance and analysis is ongoing, but most previously reported cases of myocarditis have been identified within the timeframe used in this initial analysis, which is reassuring and may be due to the lower dose of BNT162b2 given. The FDA is currently delaying a decision for authorization of Moderna’s mRNA vaccine for pediatric patients aged 12–17 years to evaluate emerging data on the risk of myocarditis in this population, which seems to have a known increased risk in men aged 18–30 years.

Based on the safety and efficacy data presented to the FDA advisory committee, members recommended that FDA authorize emergency use in the 5–11-year-old age group, and the agency concurred. Subsequently, CDC director Rochelle Wolensky endorsed the Advisory Committee on Immunization Practices (ACIP) recommendation for BNT162b2 to be recommended for this population.

CDC Strengthens Pregnancy Recommendation for COVID-19 Vaccine

Pregnant women have been hesitant to received COVID-19 vaccines because of concerns about fetal toxicity or miscarriage. While early recommendations were for pregnant women to discuss the potential for COVID-19 vaccination with their health care provider, the CDC has recently strengthened their recommendation for a number of important reasons. First, pregnant women are known to be at an increased risk of severe COVID-19 illness compared with nonpregnant women. Second, studies have shown no increased risk of miscarriage when women were vaccinated against COVID-19 before 20 weeks of pregnancy compared with baseline rates. Third, early data suggest pregnant women who receive COVID-19 vaccines are at decreased risk of acquiring SARS-CoV-2 compared with those pregnant women who were unvaccinated. In addition, babies may be protected from COVID-19 in women who have been vaccinated during pregnancy. Antibodies that are found in pregnant women are found in umbilical cord blood, suggesting passive immunity may provide benefit for the child upon delivery similar to other vaccines.

Oral Antiviral Therapy

While the vaccines are the most important tool in converting SARS-CoV-2 from pandemic to endemic status, effective and safe treatment options are important to close the loop on options to combat the virus. On the heels of positive data regarding the Merck oral therapy molnupiravir in decreasing hospitalization or death for COVID-19, Pfizer’s product known as Paxlovid has also demonstrated decreased risk of hospitalization or death in outpatients with confirmed mild-to-moderate COVID-19. Paxlovid consists of 2 medications: PF-07321332, a 3CL protease inhibitor coded for by SARS-CoV-2, and ritonavir, a well-known antiviral used primarily within human immunodeficiency virus (HIV) infections as a “booster” for other protease inhibitors. Within the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) phase 2/3 study, patients were randomized to Paxlovid or placebo twice daily for 5 days as long as they were within 5 days of laboratory-confirmed SARS-CoV-2 infection and symptom onset. A scheduled interim analysis of patients presenting within 3 days of symptoms demonstrated an 89% reduction in COVID-19–related hospitalization or death (1% vs. 6.7%; P <0.001) for Paxlovid versus placebo. Through day 28, no deaths were reported among patients receiving Paxlovid while 10 deaths occurred in the placebo group.

The FDA Antimicrobial Drugs Advisory Committee (AMDAC) meets on November 30, 2021, to discuss data supporting the use molnupiravir, which has been approved in the United Kingdom based on data similar to that to be discussed by the AMDAC. Pfizer’s oral antiviral product will likely be considered soon by the FDA AMDAC for use in a similar population. After many months of a number of failed therapies for COVID-19, it is encouraging to have 2 promising oral antiviral therapies in the pipeline for possible use in ambulatory patients with mild-to-moderate COVID-19. 

REFERENCES

1. Cohn BA, Cirillo PM, Murphy CC, et al. SARS-CoV-2 vaccine protection and deaths among US veterans during 2021. Science. 2021 Nov 4; eabm0620. doi: 10.1126/science.abm0620. Online ahead of print.
2. Barda N, Dagan N, Cohen C, et al. Effectiveness of a third dose of BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. Lancet. 2021 Oct. 29; doi: 10.1016/S0140-6736(21)02249-2. Online ahead of print.
3. Atmar RT, Lyke KE, Deming ME, et al. Heterologous SARS-CoV-2 booster vaccinations — preliminary report. Posted online October 15, 2021. https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v2.full.pdf

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