Development of COVID-19 vaccine policy — United States, 2020–2023

Abstract

COVID-19 vaccines represent a great scientific and public health achievement in the face of overwhelming pressures from a global pandemic, preventing millions of hospitalizations and deaths due to COVID-19 vaccines in the United States. Over 675 million doses of COVID-19 vaccines have been administered in the United States, and over 80% of the U.S. population has had at least 1 dose of a COVID-19 vaccine. Over the course of the COVID-19 pandemic in the United States, over one million people died from COVID-19, and over six million were hospitalized. It has been estimated that COVID-19 vaccines prevented more than 18 million additional hospitalizations and more than 3 million additional deaths due to COVID-19 in the United States.

From the beginning of the COVID-19 pandemic in 2020 through June 2023, ACIP had 35 COVID-19 focused meetings and 24 votes for COVID-19 vaccine recommendations. ACIP had the critical task of rapidly and thoroughly reviewing emerging and evolving data on COVID-19 epidemiology and vaccines, as well as making comprehensive population-based recommendations for vaccine policy and considerations for implementation through a transparent and evidence-based framework. Safe and effective COVID-19 vaccines, recommended through transparent policy discussions with ACIP, remain the best tool we have to prevent serious illness, hospitalization and death from COVID-19.

1. Introduction

COVID-19 vaccines represent a great scientific and public health achievement in the face of overwhelming pressures from a global pandemic, preventing millions of hospitalizations and deaths due to COVID-19 vaccines in the United States [1]. Development of a new vaccine requires pre-clinical research and human clinical trials, followed by review by regulatory and public health agencies. The U.S. Food and Drug Administration (FDA) is responsible for authorization or licensure of vaccines, and the U.S. Centers for Disease Control and Prevention (CDC) makes public health recommendations regarding use of vaccines for effective control of vaccine-preventable diseases in the United States. Both federal agencies have federal advisory committees that can provide public review of available data and advice to the respective agencies before regulatory actions and recommendations are made. FDA can seek guidance from the Vaccines and Related Biological Products Advisory Committee (VRBPAC)[2], and CDC can seek guidance from the Advisory Committee on Immunization Practices (ACIP)[3].

ACIP was established in 1964 and consists of up to 20 voting members who are medical and public health experts who develop recommendations on how to use vaccines and control vaccine-preventable diseases in the United States[4]. In addition to the voting members, there are 31 non-voting representatives from professional organizations and six ex-officio members from other federal agencies to offer additional perspectives. ACIP holds three regular meetings each year where members review available data, including: epidemiology, vaccine research and clinical trial results, vaccine safety and effectiveness and implementation considerations to inform the development of vaccine policy; additional meetings are scheduled as needed. Meetings are open to the public and available online via a webcast[4,5]. ACIP Work Groups, comprised of ACIP voting members, liaison members, and other expert consultants, meet as needed, to assist with data review and development of recommendation options. To make vaccine recommendations, ACIP uses the Evidence to Recommendations (EtR) Framework and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach[6]. Within the EtR framework, data are reviewed across key domains, including: public health problem, benefits and harms of the vaccine, including the GRADE-evidence assessment, patients’ values and preferences, issues of resource use, acceptability to stakeholders, feasibility of implementation, and anticipated impact on health equity. Once FDA regulatory action is taken, either issuing an Emergency Use Authorization [EUA] or approval for a vaccine product[7], ACIP can make recommendations for use of the vaccine. Informed by data presented within the EtR Framework, ACIP can vote to recommend the vaccine, recommend the vaccine based on shared clinical decision making, or not recommend the vaccine. Recommendations for shared clinical decision-making (also described as ‘may receive the vaccine’ during the COVID-19 pandemic) indicate that the vaccine is not recommended for everyone in a particular age group or an identifiable risk group but decisions about vaccination are individually based and informed by a decision process between the health care provider and the patient[8]. Guidance typically accompanies the recommendations and includes who should receive the vaccine, the number of doses a person needs for adequate protection, the optimal amount of time between doses, as well as precautions and contraindications.

COVID-19 was declared a public health emergency in the United States on January 31, 2020[9]. Operation Warp Speed was initiated in 2020 as a partnership between the U.S. government and industry to facilitate expedited COVID-19 vaccine, therapeutic, and diagnostic development, manufacturing, and distribution[10]. While vaccines were undergoing early phase development and progressing to larger clinical trials, ACIP established the infrastructure for the development of COVID-19 vaccine policy. The first COVID-19 Vaccines Work Group call occurred on April 30, 2020. Work Group members reviewed COVID-19 epidemiology and the vaccine landscape and continued to meet 2–4 times per month throughout the course of the pandemic. An additional Work Group, the COVID-19 Vaccine Safety Technical Work Group (VaST) was established to review post-authorization vaccine safety data and collaborated with the COVID-19 Vaccines Work Group; details of VaST are described by Markowitz, et al, in this supplement[11]. In June 2020, ACIP reviewed data on COVID-19, including the immunology of SARS-CoV-2, the virus that causes COVID-19, COVID-19 epidemiology, the vaccine landscape, and considerations for vaccine prioritization. Emergency ACIP meetings were subsequently held in July, August, September, October, and November 2020 to publicly review data in preparation for authorization of COVID-19 vaccines[4,12].

2. Policy for initial allocation of COVID-19 vaccines

While Operation Warp Speed and vaccine manufacturers expedited vaccine development and manufacturing, forecasts suggested the initial supply of COVID-19 vaccines would not be sufficient to meet the demand for vaccination among the U.S. population for the first few months of the national COVID-19 vaccination program[13]. In anticipation of this initial phase with limited supplies, ACIP identified four ethical principles to guide recommendations for how to allocate the initial supply of COVID-19 vaccines: 1) maximizing benefits and minimizing harms; 2) promoting justice; 3) mitigating health inequities; and 4) promoting transparency[14]. On December 1, 2020, after reviewing the ethical principles as well as COVID-19 epidemiology and burden of disease, ACIP voted that both health care personnel and residents of long-term care facilities (LTCF) be offered COVID-19 vaccine in the initial phase of the vaccination program (Phase 1a)[15]. On December 20, ACIP updated the interim vaccine allocation recommendations to include additional populations; in Phase 1b, COVID-19 vaccine would be offered to persons ages ≥ 75 years and non–health care frontline essential workers, and in Phase 1c, to persons ages 65–74 years, persons ages 16–64 years with high-risk medical conditions, and essential workers not included in Phase 1b[16]. As most persons from the initial phases were vaccinated and supply increased, jurisdictions could progress to Phase 2, which included vaccinating all persons ages ≥ 16 years. Table 1 details the timeline of COVID-19 vaccine policy decisions.

Table 1.

Timeline of COVID-19 vaccine policy decisions.

Date	Manufacturer	Age	Population (if further specified beyond age)	Recommendations1
Policy for initial allocation of COVID-19 vaccines
December 1, 2020			Phase 1a: Healthcare workers and Long-term care facility (LTCF) residents
December 20, 2020			Phase 1b: Persons ages ≥ 75 years and non-healthcare frontline essential workers
			Phase 1c: Persons ages 65–74 years; persons ages 16–64 years with high-risk medical conditions; essential workers not included in Phase 1b
Initial Recommendations for COVID-19 vaccines
December 12, 2020	Pfizer-BioNTech	≥16 years		2-dose primary series
December 19, 2020	Moderna	≥18 years		2-dose primary series
February 28, 2021	Janssen	≥ 18 years		Single dose primary series
Expansion of age indications
May 12, 2021	Pfizer-BioNTech	12–15 years		2-dose primary series
November 2, 2021	Pfizer-BioNTech	5–11 years		2-dose primary series
June 23, 2022	Moderna	6–17 years		2-dose primary series
June 18, 2022	Moderna	6 months-5 years		2-dose primary series
	Pfizer-BioNTech	6 months-4 years		3-dose primary series
Initial booster dose recommendations
September 22, 2021	Pfizer-BioNTech	≥ 18 years	Persons aged ≥ 65 years, residents of LTCFs ≥ 18 years or persons aged 50–64 years with underling medical conditions	Single booster dose
	Pfizer-BioNTech	≥ 18 years	Persons 18–49 years with underlying medical conditions may receive a booster dose.	Single booster dose may be given
			CDC Director added persons aged 18–64 years at increased risk for SARS-CoV-2 exposure and transmission because of occupational or institutional setting
October 21, 2021	Moderna	≥ 18 years	Populations previously recommended for a booster dose	Single booster dose
October 21, 2021	Janssen	≥ 18 years	Persons who received a Janssen COVID-19 vaccine	Single booster dose
November 19, 2021	mRNA vaccines	≥ 50 years		Single booster dose
	mRNA vaccines	18–49 years		Single booster dose may be given2
January 5, 2022	Pfizer-BioNTech	12–15 years		Single booster dose
May 19, 2022	Pfizer-BioNTech	5–11 years		Single booster dose
April 20, 2022	mRNA vaccines	≥ 50 years		Second booster dose may be given
	mRNA vaccines	≥ 12 years	Persons with immunocompromising conditions	Second booster dose may be given
Updated (Bivalent) vaccine recommendations
September 1, 2022	Pfizer-BioNTech	≥ 12 years		Single bivalent booster dose
	Moderna	≥ 18 years		Single bivalent booster dose
October 12, 2022	Pfizer-BioNTech	5–11 years		Single bivalent booster dose
December 8, 2022	Pfizer-BioNTech	6 months-4 years		Bivalent dose as third dose in a 3-dose primary series
	Moderna	6 months-5 years		Single bivalent booster dose
March 14, 2023	Pfizer-BioNTech	6 months-4 years	Children who received 3 monovalent doses of Pfizer-BioNTech as a primary series	Single bivalent booster dose
April 19, 2023	Pfizer-BioNTech	≥ 5 years		Single bivalent dose, regardless of previous vaccines received
		6 months-4 years		Multi-dose initial series that includes at least one bivalent vaccine, depending on age, number and type of prior COVID-19 vaccine doses received
	Moderna	≥ 6 years		Single bivalent dose, regardless of previous vaccines received
		6 months-5 years		Multi-dose initial series that includes at least one bivalent vaccine, depending on age, number and type of prior COVID-19 vaccine doses received
	mRNA vaccines	≥ 65 years		Second booster dose may be given
		≥ 6 months	Persons with immunocompromising conditions	Second booster dose may be given
Expansion to other platforms: Protein subunit vaccine
July 19, 2022	Novavax	≥ 18 years		2-dose primary series
August 22, 2022	Novavax	12–17 years		2-dose primary series
October 19, 2022	Novavax	≥ 18 years	Persons unwilling or unable to receive an updated (bivalent) COVID-19 vaccine booster dose and not received a previous booster dose	Single booster dose

¹Unless otherwise specified, CDC and ACIP recommended the vaccine for everyone in the population specified (i.e. “should receive” the vaccine).

²CDC expanded this recommendation on November 29, 2021, stating everyone ≥ 18 years should receive a mRNA COVID-19 vaccine booster dose.

3. Initial recommendations for COVID-19 vaccines

In December 2020, FDA authorized two mRNA COVID-19 vaccines for use in the United States[17,18]. ACIP held an emergency meeting on December 11–12, 2020, immediately after the authorization, to discuss the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2; Pfizer, Inc; Philadelphia, Pennsylvania), which is a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine encoding the prefusion spike glycoprotein of the ancestral strain of SARS-CoV-2, given as a 2-dose primary series separated by 21 days. Updated COVID-19 epidemiology, as well as manufacturer clinical trial data, and CDC’s GRADE and the EtR Framework were presented to ACIP at the emergency meeting, and on December 12, 2020, ACIP voted to recommend use of the Pfizer-BioNTech COVID-19 Vaccine as a 2-dose series in individuals ages ≥ 16 years[19].

The following week, ACIP held an emergency meeting on December 19–20, 2020 to discuss the Moderna COVID-19 Vaccine (mRNA1273; ModernaTX, Inc; Cambridge, Massachusetts), which is also a lipid nanoparticle-encapsulated, nucleoside-modified mRNA vaccine encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2 (ancestral strain), given as a 2-dose series separated by 28 days. Manufacturer clinical trial data, GRADE, and the EtR Framework were also reviewed. ACIP voted to recommend use of the Moderna COVID-19 Vaccine as a 2-dose series in individuals ages ≥ 18 years[20].

On February 27, 2021, FDA authorized the third COVID-19 vaccine [21], and on February 28, 2021, ACIP held an emergency meeting to review data for the Janssen COVID-19 Vaccine (Ad.26.COV2.S; Janssen Biotech, Inc, a Janssen Pharmaceutical company, Johnson & Johnson; New Brunswick, New Jersey), a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector vaccine, encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2 (ancestral strain), given as a single dose. Since it required only a single dose and could be stored and transported at refrigerator temperatures, the Janssen COVID-19 Vaccine allowed for expanded availability of COVID-19 vaccines. ACIP voted to recommend use of the Janssen COVID-19 Vaccine as a single dose in individuals ages ≥ 18 years[22].

In just over a year from COVID-19 being declared a public health emergency, FDA authorized, and CDC recommended three different COVID-19 vaccines with high efficacy against the contemporaneously circulating SARS-CoV-2 virus. Large clinical trials were conducted, enrolling 30,000–40,000 individuals[23–25]. In addition, there was a strong emphasis on recruiting a diverse population for the clinical trials, including racial and ethnic diversity as well as older adults and adults with underlying medical conditions. At that time, ACIP did not state a product preference; persons were recommended to receive the ACIP-recommended COVID-19 vaccine primary series available to them [22]. According to guidance from FDA[26], the initial EUAs were based on an interim analysis from the Phase III clinical trials with a median of 2-month follow-up duration, in addition to accumulated data from Phase 1 and 2 studies.

4. Safety concern with Janssen COVID-19 Vaccine: thrombosis with thrombocytopenia syndrome

After authorization, COVID-19 vaccines have been monitored under the most intense safety monitoring in U.S. history; details of the safety surveillance are described by Gee et al, in the supplement[27]. On April 13, 2021, based on initial reports from vaccine safety surveillance systems, CDC and FDA recommended a pause in the use of the Janssen COVID-19 Vaccine after reports of six U.S. cases of cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare but potentially life-threatening thromboembolic syndrome, among Janssen COVID-19 Vaccine recipients[28]. The European Medicines Agency announced a possible link to a similar clinical presentation with the AstraZeneca COVID-19 Vaccine, also an adenovirus-vectored vaccine[29]. This clinical presentation was ultimately termed thrombosis with thrombocytopenia syndrome (TTS) in the United States[30]. In addition to data reviews by VaST[11], two emergency ACIP meetings were rapidly convened to review reported cases of TTS and consider updated recommendations for use of the Janssen COVID-19 Vaccine in the United States. Table 2 describes ACIP meetings for safety-focused review of data and impacts on vaccine recommendations.

Table 2.

ACIP meetings for safety-focused review of data.

Date	Vaccine of focus	Age	Topic	Outcome
April 14, 2021	Janssen	≥18 years	Thrombosis with Thrombocytopenia Syndrome (TTS) after receipt of Janssen COVID-19 vaccine	Continued pause for additional review of data
April 23, 2021	Janssen	≥18 years	Additional data and benefit-risk analysis of TTS and COVID-19 vaccines	Reaffirmed recommendations, with information around benefit-risk
June 22, 2021	mRNA vaccines	≥18 years	Myocarditis after mRNA vaccines	Reaffirmed recommendations, with information around benefit-risk
July 22, 2021	All COVID-19 vaccines	≥12 years	Review of Guillain-Barré syndrome (GBS) and TTS after Janssen vaccination and myocarditis after mRNA vaccination	Reaffirmed recommendations, with information around benefit-risk
December 16, 2021	Janssen	≥18 years	Updates to TTS after Janssen vaccination	Preferential use of mRNA vaccines over the Janssen vaccine

On April 14, 2021, ACIP reviewed information on the initial 6 cases of TTS following nearly 7 million doses of Janssen COVID-19 Vaccine administered. At that time, ACIP recommended the Janssen COVID-19 Vaccine pause be continued for two additional weeks to allow for additional review of data, including assessment of the benefit-risk balance. Details of the TTS cases have been described elsewhere[30].

On April 23, 2021, ACIP met to review additional data, including further case ascertainment of TTS events after Janssen COVID-19 Vaccine as well as a formal benefit-risk assessment. This assessment included estimates of both population- and individual-level risks as well as benefits of receiving a Janssen COVID-19 Vaccine[31]. After a discussion of the benefits and risks of resuming vaccination, ACIP reaffirmed its interim recommendation for use of the Janssen COVID-19 Vaccine in all persons ages ≥ 18 years under the FDA’s EUA, where a warning was added that rare clotting events might occur after vaccination, primarily among women ages 18–49 years[32]. Patient and provider education about the risk for TTS with the Janssen COVID-19 Vaccine, especially among women ages < 50 years, as well as the availability of alternative COVID-19 vaccines, was important to guide vaccine decision-making and ensure early recognition and clinical management of TTS[33].

5. Expansion of age indications for COVID-19 vaccines

The initial authorizations for COVID-19 vaccines focused on individuals ages ≥ 16 years (Pfizer-BioNTech COVID-19 Vaccine) or ≥ 18 years (Moderna and Janssen COVID-19 Vaccines). Soon after the initial clinical trials were completed, studies began to evaluate COVID-19 vaccines in adolescents[34,35] and eventually younger children [36–39]. ACIP met to review available data following FDA authorizations for expanded age indications throughout 2021 and 2022. While the studies addressed narrower age groups for vaccine recommendations, clinical trials transitioned to include not only clinical efficacy data, but also immunobridging data, which is the comparison of neutralizing antibody levels postvaccination in one age group (e.g., adolescents) with those in a population in whom clinical efficacy had been demonstrated (e.g., young adults). Expansion of the age indications to include children and adolescents were initially authorized for the Pfizer COVID-19 Vaccines, and subsequently included the Moderna COVID-19 Vaccines.

On May 12, 2021, ACIP reviewed available data among adolescents, and voted to recommend use of the Pfizer-BioNTech COVID-19 Vaccine in adolescents ages 12–15 years. Vaccine efficacy was also supported by immunobridging data that indicated the immune response in adolescents ages 12–15 years was at least as high as the response observed in persons ages 16–25 years. These recommendations were made as adolescents represented a growing proportion of new COVID-19 cases, and identification of multisystem inflammatory syndrome in children (MISC), a severe hyperinflammatory syndrome occurring several weeks after acute SARS-CoV-2 infection, which impacted adolescents[40]. On November 2, 2021, ACIP reviewed data and voted on use of the 2-dose Pfizer-BioNTech COVID-19 Vaccine for children ages 5–11 years. At that time, approximately 1.9 million COVID-19 cases and 8,300 hospitalizations among U.S. children ages 5–11 years had been reported to CDC [41]. In addition to high vaccine efficacy, the immunobridging data indicated that the immune response to the Pfizer-BioNTech COVID-19 Vaccine in children ages 5–11 years was at least as high as the response observed in persons ages 16–25 years[41]. Data to inform the expansion of COVID-19 vaccines in children and adolescents ages 6–17 years to include the Moderna COVID-19 Vaccine was presented to ACIP on June 23, 2022. Again, studies included both clinical efficacy and immunobridging; the immune response among children ages 6–11 years and adolescents ages 12–17 years was noninferior to adults ages 18–25 years. Two vaccine options in the pediatric population expanded availability and allowed parents and providers a choice in COVID-19 vaccines[42].

On June 17–18, 2022, ACIP met to review data for both mRNA vaccine products in young children and voted to recommend the use of the Moderna COVID-19 Vaccine in children ages 6 months–5 years and the Pfizer-BioNTech COVID-19 Vaccine in children ages 6 months–4 years[43]. At that time, approximately 2 million COVID-19 cases, 20,000 hospitalizations, and 200 deaths from COVID-19 had been reported among U.S. children ages 6 months–4 years; approximately one half (51 %–54 %) of children in this age group with a COVID-19–associated hospitalization had no underlying health conditions, highlighting the risk for severe COVID-19 even among young children without underlying health conditions[43]. Clinical trials for children 6 months through 4 or 5 years of age represented the first trials for COVID-19 vaccines conducted while the Omicron B.1.1.529 variant of SARSCoV-2 was the predominant circulating variant during the trial. For the Moderna COVID-19 Vaccine, a lower vaccine efficacy against symptomatic COVID-19 was noted compared to clinical trials in adults conducted earlier in the pandemic[39,43]. However, efficacy was consistent with real-world vaccine effectiveness studies in those ages ≥ 5 years during the Omicron predominance[44]. In addition, the immune response to 2 doses of the Moderna COVID-19 Vaccine in children ages 6–23 months and 2–5 years was at least as high as the response observed in young adults ages 18–25 years[43]. A clinical trial was also conducted to evaluate the immunogenicity, efficacy, and safety of the Pfizer-BioNTech COVID-19 Vaccine among children 6 months through 4 years of age[37]. The protocol initially specified 2 doses of vaccine or saline placebo separated by an interval of 3 weeks. Based on an interim analysis where the predefined criteria for immunobridging and efficacy of the trial were not met after 2 doses, a protocol amendment was implemented, to include a third dose of either vaccine or saline placebo, administered ≥ 56 days after dose 2. After this third dose, the efficacy and immunobridging endpoints were met; the measure of immune response to 3 doses of the Pfizer-BioNTech COVID-19 Vaccine in children ages 6 months–4 years without evidence of previous SARS-CoV-2 infection was at least as high as the response observed in persons ages 16–25 years[37,43]. While uptake of COVID-19 vaccines among children and adolescents lagged behind older adults, updated benefit-risk assessments demonstrated the impact of vaccination in this population. While the absolute benefits depend on the incidence of disease, it was estimated that a COVID-19 vaccine primary series in children and adolescents could prevent 248–944 COVID-19-associated hospitalizations over 6 months, per million primary series given (based on hospitalization rates from December 2022)[45].

6. Safety-focused reviews

Vaccine safety data have always been critical for public discussions of vaccine policy. Details of the vaccine surveillance systems and review of the data by VaST have been detailed elsewhere in this supplement [11,27]. In addition, ACIP has held several ACIP meetings specifically focused on vaccine safety data updates, the benefit/risk balance of COVID-19 vaccines, and if any changes to vaccine policy were needed, with the details provided in Table 2.

On June 22, 2021, after reports of myocarditis and pericarditis in mRNA vaccine recipients, ACIP met to discuss cases of myocarditis and pericarditis as well as the benefits and risks of mRNA COVID-19 vaccination in the United States. Myocarditis is an inflammation of the heart muscle; if it is accompanied by pericarditis, an inflammation of the pericardium, it is referred to as myopericarditis. Clinical details of myocarditis after mRNA COVID-19 vaccines are described elsewhere [46]. After reviewing available evidence for the risks of myocarditis, ACIP determined that the benefits of using mRNA COVID-19 vaccines (prevention of COVID-19 disease and associated hospitalizations, ICU admissions, and deaths) clearly outweighed the risks (possible myocarditis cases after vaccination) in all populations, including adolescents and young adults[47]. However, the balance of benefits and risks varied by age and sex because cases of myocarditis were primarily identified among males ages < 30 years, and the risks of poor outcomes related to COVID-19 increase with age. The EUAs were modified to include information on myocarditis after receipt of mRNA COVID-19 vaccines[48–50]. In addition, CDC developed patient and provider education materials about the possibility of myocarditis and symptoms of concern, to ensure prompt recognition and management of myocarditis [51,52].

ACIP also highlighted the benefits of an extended primary series interval for persons ages ≤ 18 years. Several studies in adolescents and adults indicated the small risk for myocarditis associated with mRNA COVID-19 vaccines might be reduced, and peak antibody responses and vaccine effectiveness might be increased with an interval longer than 4 weeks between the 2 primary series doses[53–56]. Based on the evidence presented to ACIP, CDC provided guidance that an 8-week interval between primary series doses might be optimal for some adolescents and adults, especially for males ages 12–39 years[57].

On July 22, 2021, ACIP met to discuss three medical conditions that were reported in temporal association with receipt of COVID-19 vaccines. Updates were provided for TTS after receipt of the Janssen COVID-19 Vaccine, and myocarditis after mRNA COVID-19 vaccines. In addition, data regarding cases of Guillain-Barré syndrome (GBS) reported after Janssen COVID-19 Vaccine were discussed. GBS is a rare neurological disorder in which the immune system damages nerves, causing muscle weakness and/or paralysis. Although rare, GBS was reported at a higher-than-expected rate in the 42 days after Janssen COVID-19 vaccination and a warning was added to FDA’s EUA fact sheets[58]. Based on a comprehensive review of existing data, in the context of COVID-19 epidemiology at the time, ACIP concluded that the benefits of vaccinating all recommended age groups with either the Janssen COVID-19 Vaccine or mRNA COVID-19 vaccines outweighed the risks for vaccination, including the risks for GBS and TTS after Janssen COVID-19 vaccination, or myocarditis after mRNA COVID-19 vaccination; in addition, continuing safety monitoring of serious adverse events after COVID-19 vaccination was critical and individuals should be informed about these potential harms and the use of COVID-19 vaccines[59].

ACIP continued to closely monitor the benefit-risk balance of COVID-19 vaccines. Through ongoing safety surveillance and review of reports from the Vaccine Adverse Event Reporting System (VAERS), additional cases of TTS after receipt of Janssen COVID-19 Vaccine, including deaths, were identified. On December 16, 2021, ACIP held an emergency meeting to review updated data on TTS and an updated benefit-risk assessment. Importantly, although public health messaging concerning the risk associated with the Janssen COVID-19 vaccine and clinical guidance for management and treatment of TTS was provided in April 2021, the proportion of deaths among reported TTS cases did not decline[60]. Based on a comprehensive review of existing data, ACIP concluded that because of both higher vaccine effectiveness of mRNA COVID-19 vaccines and more serious rare safety issues associated with the Janssen vaccine, the benefit-risk balance for mRNA COVID-19 vaccines is more favorable than that for Janssen COVID-19 vaccine. In the setting of wide availability of mRNA COVID-19 vaccines in the United States, ACIP made a preferential recommendation for mRNA COVID-19 vaccines over the Janssen COVID-19 Vaccine[60]. On May 22, 2023, Janssen requested the voluntary withdrawal of the EUA for the Janssen COVID-19 vaccine, and on June 1, 2023 FDA withdrew the EUA[61,62].

7. Initial (monovalent) booster dose recommendations

During fall of 2021, the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2 became the predominant circulating U.S. strain, leading to an increase in cases and hospitalizations[63,64]. In addition, waning vaccine effectiveness with increasing time since the COVID-19 vaccine primary series and decreased effectiveness against the Delta variant were noted, especially against symptomatic infection[65]. COVID-19 vaccine policy evolved rapidly throughout late 2021, reflecting evolving COVID-19 epidemiology and emerging vaccine effectiveness data throughout this time period. FDA authorized the Pfizer-BioNTech COVID-19 Vaccine as a booster dose for certain populations on September 22, 2021[66]. ACIP met September 22–23, 2021, and reviewed COVID-19 epidemiology, primary series vaccine effectiveness, as well as safety, immunogenicity, and effectiveness of booster doses. These data were also used to inform a benefit-risk assessment of Pfizer-BioNTech COVID-19 Vaccine booster doses that was presented to ACIP. After reviewing all available data, ACIP recommended that persons ages ≥ 65 years, residents ages ≥ 18 years in long-term care settings, and persons ages 50–64 years with certain underlying medical conditions should receive a single Pfizer-BioNTech COVID-19 Vaccine booster dose and that persons ages 18–49 years with certain underlying medical conditions may receive a single Pfizer-BioNTech COVID-19 Vaccine booster dose based on individual benefits and risks. CDC further recommended that persons ages 18–64 years at increased risk for SARS-CoV-2 exposure and transmission due to occupational or institutional setting may receive a single Pfizer-BioNTech COVID-19 Vaccine booster dose based on individual benefits and risks[67].

ACIP met again on October 21, 2021, to review additional data from Moderna and Janssen, as well as information from the National Institutes of Health regarding heterologous booster doses[68]. FDA authorized both Moderna and Janssen COVID-19 Vaccines to be used as booster doses[69] and ACIP expanded the booster recommendations to include a Moderna COVID-19 Vaccine booster dose, for the populations previously recommended to receive a Pfizer COVID-19 Vaccine booster dose. In addition, ACIP recommended that all people ages ≥ 18 years who received a single-dose Janssen COVID-19 Vaccine should receive a booster dose. This recommendation replaced the September 2021 ACIP recommendation for only the Pfizer-BioNTech COVID-19 Vaccine booster doses and allowed for heterologous booster doses (the vaccine received as a booster could differ from the COVID-19 vaccine received as the primary series)[67].

The benefit-risk balance of booster doses was further updated with additional safety data, as well as increases in COVID-19 cases and hospitalizations into late 2021. ACIP discussed these updates and acknowledged the complexity of the booster recommendations at the November 19, 2021, ACIP meeting. At that meeting, ACIP voted to simplify the vaccine policy, recommending that everyone ages 18–49 years may receive a mRNA COVID-19 vaccines booster, while everyone ages ≥ 50 years should receive a mRNA COVID-19 vaccine booster dose [70]. CDC expanded this recommendation later in November 2021, stating everyone ≥ 18 years should receive a mRNA COVID-19 vaccine booster dose[71].

In early 2022, COVID-19 cases had surged to a 7-day average of nearly 500,000 daily cases as the Omicron B.1.1.529 variant became the predominant SARS-CoV-2 variant in the United States[72]. In the setting of Omicron, substantially lower vaccine effectiveness and faster waning of vaccine effectiveness after an initial primary series was noted in all populations, including against more severe outcomes, compared to effectiveness seen with Delta variant[73]. ACIP expanded recommendations for a single booster dose of a Pfizer-BioNTech COVID-19 Vaccine to include adolescents ages 12–15 years at an ACIP meeting January 5, 2022[74,75], and further expanded the recommendations to include children ages 5–11 years at an ACIP meeting May 19, 2022[76,77].

Throughout the COVID-19 pandemic, older adults and persons with immunocompromising conditions have been at higher risk for severe disease from COVID-19[78,79]. In addition, some populations are at risk of sub-optimal immune response to vaccines due either to immune senescence among older adults, or immunocompromising medications or conditions among individuals of all ages[80–83]. To optimize protection for these vulnerable populations throughout the pandemic, COVID-19 vaccine policy evolved to allow for additional vaccine doses in these populations. On August 13, 2021, ACIP voted for an additional mRNA primary series dose in persons with moderate to severe immunocompromising conditions[67]. ACIP also discussed second COVID-19 mRNA vaccine booster doses on April 20, 2022, and agreed with CDC recommendations that individuals ages ≥ 50 years or persons with an immunocompromising condition may receive a second COVID-19 mRNA vaccine booster dose[84,85].

8. Updated (bivalent) COVID-19 vaccines

In 2022, the Omicron variant of SARS-CoV-2 continued to be the primary circulating variant, with many sub-variants, including BA.1, and BA.4 or BA.5 (which share the same spike protein); newer sub-variants were found to evade antibodies more than earlier variants [86,87]. Effectiveness of a third (booster) dose of COVID-19 vaccines provided significant additional protection against infection and severe disease in all ages studied but waning of protection was noted[44,88]. In addition, by August 2022, most individuals had not received a COVID-19 vaccine in at least 6 months[89]. Because COVID-19 vaccines demonstrated decreased effectiveness while the Omicron variant predominated, bivalent booster doses were considered, with a goal to expand the immune response to the circulating Omicron variant, and improve protection conferred by COVID-19 vaccines against severe disease. Bivalent Pfizer-BioNTech and Moderna booster vaccines contained the same total amount of mRNA encoding spike protein antigen as the previous monovalent vaccines, divided equally between the ancestral and Omicron BA.4/BA.5 strains.

On September 1, 2022, ACIP reviewed data regarding the epidemiology of COVID-19 vaccine, as well as immunogenicity and safety of bivalent COVID-19 vaccines and a review of COVID-19 vaccine safety. While details of the data reviewed are provided elsewhere[89], after reviewing the totality of available data, ACIP recommended bivalent mRNA booster vaccines for persons ages ≥ 12 years (Pfizer-BioNTech) and adults ages ≥ 18 years (Moderna)[90]. Vaccine policy for bivalent mRNA COVID-19 vaccines continued to evolve through 2022 and 2023 to allow expanded access to bivalent vaccines and to simplify COVID-19 vaccine recommendations. In October 2022, CDC, with ACIP input, expanded the recommendation for a bivalent Pfizer-BioNTech booster dose for persons ages ≥ 5 years and a bivalent Moderna COVID-19 Vaccine booster dose for persons ages ≥ 6 years[91,92]. In December 2022, following changes to the FDA authorizations, CDC recommended a bivalent Moderna COVID-19 Vaccine booster dose for children ages 6 months–5 years; a third primary dose of bivalent Pfizer-BioNTech Vaccine for children ages 6 months–4 years was also recommended after receipt of 2 primary doses of monovalent Pfizer-BioNTech Vaccine[93]. In March 2023, CDC recommended a bivalent Pfizer-BioNTech COVID-19 Vaccine booster dose for children ages 6 months–4 years who received a 3-dose monovalent Pfizer-BioNTech COVID-19 Vaccine primary series.

ACIP continued to review data and evaluate the COVID-19 vaccine program in the context of evolving epidemiology. The initial COVID-19 vaccine primary series recommendations were made in light of a highly susceptible, immune naive population, with limited treatment options. Increases in population-level immunity, acquired through both vaccine and infection, SARS-CoV-2 virus evolution, availability of effective anti-viral treatments, changing COVID-19 epidemiology, decreasing hospitalization rates, coupled with continued efforts for simplification of vaccine recommendations and increased flexibility of vaccine recommendations for vulnerable populations, led to evidence-based updates in vaccine policy. By late 2022, an estimated 96.4 % of persons aged ≥ 16 years had SARS-CoV-2 antibodies from previous infection or vaccination, including 22.6 % from infection alone, 26.1 % from vaccination alone, and 47.7 % had antibodies from both infection and vaccination [94]. In April 2023, CDC recommended a single dose of a bivalent mRNA vaccine for all persons ages ≥ 6 years, regardless of prior history of receipt of original COVID-19 vaccines. In addition, to harmonize vaccine composition for all available mRNA COVID-19 vaccines, children ages 6 months through 4 or 5 years of age were recommended for 2 or 3 doses of COVID-19 vaccines, to include at least one dose of a bivalent COVID-19 vaccine, based on their age and previous COVID-19 vaccines received [95].

9. Expansion to other platforms: Protein subunit COVID-19 vaccines

Initial COVID-19 vaccine recommendations focused on either mRNA or adenovirus vector vaccine platforms. Expansion to other vaccine platforms allowed for broader access, especially for people with allergies or precautions to receiving other COVID-19 vaccines. The Novavax COVID-19 Vaccine (NVX-CoV2373; Novavax, Inc; Gaithersburg, Maryland) is a monovalent recombinant spike (rS) protein nanoparticle vaccine with Matrix-M adjuvant, given as a 2-dose series separated by 28 days, targeting the ancestral SARS-CoV-2 strain. On July 19, 2022, ACIP reviewed data regarding the Novavax COVID-19 Vaccine and voted to recommend the vaccine as a 2-dose primary series[96]. FDA later expanded the authorization for a 2-dose primary series to include individuals ages 12 years and older[97], and CDC updated the recommendations to include adolescents[98]. The adjuvanted, protein subunit-based Novavax COVID-19 vaccine provided an additional option for unvaccinated adolescents and adults, increasing flexibility for the public and for vaccine providers. On October 19, 2022, CDC also provided recommendations for a monovalent Novavax COVID-19 Vaccine booster dose[99]. A Novavax COVID-19 Vaccine booster dose was recommended for people ages ≥ 18 years who were unable or unwilling to receive an updated (bivalent) Pfizer or Moderna COVID-19 booster and had not received a previous booster dose[100].

10. Challenges

While a monumental effort was expended to create and update COVID-19 vaccine policy since 2020, several challenges have existed. ACIP and CDC needed to make recommendations with limited and rapidly evolving information to create timely vaccine policy during a public health emergency. The changing epidemiology throughout the course of the pandemic and SARS-CoV-2 virus evolution drove changes at timelines never before seen in vaccine policy. While ACIP typically meets three times a year, numerous emergency meetings were required to address the evolving virus and need to update vaccine recommendations. In addition, unprecedented public attention was focused on vaccine policy, at times with over 50,000 individuals streaming ACIP meetings and over 125,000 public comments received for a single meeting.

Next, U.S. vaccine policy had to address a population with ever-increasingly diverse immunological experience with vaccine and/or infection, as number of prior COVID-19 infections and vaccination histories in individuals expanded. Over time, the desire for simple recommendations increased, but the ability to provide singular population-level vaccine recommendations became increasingly difficult.

While the initial COVID-19 vaccine recommendations were informed by large clinical trials that included older adults and those with underlying medical conditions, data for COVID-19 vaccines in other populations were unavailable until months or years later. In addition, the clinical trials for the initial doses of COVID-19 vaccines focused on efficacy against SARS-CoV-2 infection as a primary endpoint. Clinical trial endpoints for subsequent booster doses focused on antibody levels, bridging to antibody responses seen after completion of a primary series, since a correlate of protection has not been established for SARS-CoV-2. As a result, clinical efficacy data for booster doses were unavailable at the time of authorization, especially in the setting of emerging SARS-CoV-2 variants and varying time since prior vaccination. Post-authorization real-world effectiveness studies were critical to address this gap but were limited by disease incidence and vaccine uptake[101]. Clinical trials evaluating vaccine efficacy, as well as a rapid expansion to include additional populations such as young children, pregnant persons, and immunocompromised persons, can help inform vaccine policy in future pandemics.

Communication around the evolving vaccine policies and associated clinical guidance was a challenge throughout the pandemic. Frequent changes in recommendations and vaccine products likely impacted providers and public confidence in COVID-19 vaccines and accompanying recommendations[102,103]. The public and healthcare providers were overwhelmed at times with information regarding evolving COVID-19 testing, isolation and quarantine, COVID-19 treatment, and other non-pharmaceutical intervention recommendations. In addition, increased vaccine-specific communication may have inadvertently added to COVID-19 message fatigue. In many instances, the data to inform vaccine recommendations were complicated, evolved over time, and were difficult to distill into simple messages, including complex analyses to evaluate safety signals, immunobridging data, antigenic cartography and genomic surveillance, and nuances of relative versus absolute vaccine effectiveness data.

Vaccine policy throughout the pandemic has had unique legal constraints. As previously stated, all COVID-19 vaccines were provided initially under EUAs from the FDA. The Public Readiness and Emergency Preparedness (PREP) Act authorizes the Secretary of Health and Human Services to issue a Declaration to provide liability protections to certain individuals for vaccines and other medical countermeasures[104]. While both the EUAs and the PREP Act were necessary and provided rapid availability as well as broad distribution and access for COVID-19 vaccines, testing, and treatments, they required regulatory and policy alignment. Due to these limitations, ACIP was unable to make recommendations for vaccines that differed or were broader than FDA indications (typically called “off-label recommendations”), as it can with other vaccines. This was challenging in certain populations for whom data were limited to inform vaccine authorizations, such as immunocompromised people. This unique legal framework often required ACIP to meet within hours to days after FDA’s authorizations. While the process can vary by agency, FDA and CDC typically review similar data regarding vaccine safety, efficacy and immunogenicity; this requires close collaboration between the two agencies. However, the close timing of vaccine authorization and recommendations occasionally required emergency meetings with little prior notice and limited the ability for immunization programs, healthcare providers and health systems to plan for changes.

And finally, multiple federal stakeholders were involved in COVID-19 vaccine development, authorization, recommendation, and distribution. While this unprecedented collaboration allowed for over 980 million COVID-19 vaccines to be distributed across the United States, it also required broad and complex coordination with limited time. The well-established process for vaccine policy had to rapidly adapt to include not only evolving recommendations with newly emerging data, but also a variety of new partners with vaccine policy development.

11. Successes and Lessons learned

From the beginning of the COVID-19 pandemic in 2020 through June 2023, ACIP had 35 COVID-19 focused meetings and 24 votes for COVID-19 vaccine recommendations. Throughout these meetings there were 265 presentations, including presentations focused on clinical trial data, updates to COVID-19 epidemiology, vaccine safety and effectiveness, and clinical considerations for implementation. The discussions at ACIP were informed by 117 Work Group meetings. For comparison, in a typical (i.e. non-pandemic) 3-year period, there would be 9 ACIP meetings overall, and up to 30–40 vaccine-specific Work Group calls. Expanding ACIP meetings from in-person to virtual, while still maintaining transparency through live-streaming, allowed for frequent public meetings to address the expanding COVID-19 vaccine policy questions. In addition, the ACIP meetings included presentations of new and emerging data and allowed for public discussions of vaccine policy, viewed in real-time by thousands of individuals. Traditionally, ACIP and CDC vaccine recommendations are published in CDC’s Morbidity and Mortality Weekly Report (MMWR) within a year of the vote[105]. Rapid publication of MMWR Policy Notes summarizing data and the outcome of ACIP meetings, often within several days of the vote, were critical to disseminating information around new recommendations; online tables of the Evidence to Recommendation Framework presented at the meeting were shared in real-time as well[106]. While timelines were compressed due to the public health urgency, the established vaccine policy process and framework was maintained, but also able to evolve and accommodate the challenges posed during a global pandemic.

To accompany the initial COVID-19 vaccine recommendations, CDC published detailed clinical guidance for vaccine providers for the use of COVID-19 vaccines in the United States[107]. The guidance was first published in December 2020. Since then, the guidance webpage has had over 50 updates and over 20 million page views. In addition, CDC provided clinical guidance for prevention and management of vaccine administration errors, including provider and jurisdictional support as needed. CDC has also published over 100 educational materials with over six million page views and downloads for job aids[108]. Multiple training modules were created and awarded over 700,000 continuing education credits to healthcare providers[109]. To respond to public and healthcare providers inquiries, CDC created 66 prepared responses about vaccine recommendations, which were used approximately 1 million times.

A focus on ethics and equity continues to be an important aspect of COVID-19 vaccine policy. Experts in ethics and equity were included as members of the COVID-19 vaccines Work Group, and an equity domain was added into the structure of EtR; ultimately, the EtR used by the COVID-19 vaccines Work Group was adapted to consider the evidence relevant to equity within each domain of the EtR. Through this intentional focus on equity, data were presented to inform equitable recommendations, not only including burden of disease in diverse populations, but also survey data for intent to vaccinate, doses administered, and strategies to improve uptake across populations. Disparities were noted in the initial COVID-19 vaccination coverage among minority racial and ethnic groups; these disparities narrowed after the first year of the vaccination program[110]. Substantial programmatic efforts to provide equitable access to COVID-19 vaccines during this time period might have contributed to closing the coverage gap. However, disparities by race and ethnicity were noted throughout assessments of booster dose coverage[111]. A multifaceted approach will be necessary to have continued impact on vaccine uptake in disproportionately affected communities, to narrow the racial and ethnic as well as socioeconomic disparities observed during the COVID-19 pandemic[112].

A standardized benefit-risk assessment framework was developed and updated frequently[31]. When safety signals were identified, this framework provided a mechanism to rapidly compare the direct benefits and risks of COVID-19 vaccination to inform COVID-19 vaccine policy in the setting of evolving data. The assessments were adjusted as new information, such as changing SARS-CoV-2 epidemiology or risk profiles, became available. The method was shared with other global vaccine policy makers, as well as FDA colleagues[113], and can hopefully continue to inform discussions of the balance of benefits and risks of vaccination across other vaccine-preventable diseases.

Throughout the pandemic, surveillance, vaccine effectiveness, and other data were rapidly evolving and highlighted the need for partnerships to provide the most recent data for vaccine policy. While many partnerships were important to ACIP discussions, a few are highlighted here. A collaboration between the University of Iowa and CDC, with assistance from RAND, produced numerous surveys among patients, parents and providers regarding COVID-19 vaccine intentions, concerns, and attitudes that were presented within the EtR Framework at ACIP [114,115]. The COVID-19 Scenario Modeling Hub, a partnership between academic modeling groups and CDC, aggregated modeling projections across various groups and was able to estimate the impact of different policy options that directly informed the use of booster doses [116]. The Coronavirus Disease 2019 (COVID-19) Hospitalization Surveillance Network (COVID-NET) conducts population-based surveillance for laboratory-confirmed COVID-19-associated hospitalizations among children and adults[117]. As a focus of COVID-19 vaccine policy was prevention of severe disease, COVID-NET data provided near real-time updates for hospitalization rates and was an important source of data for the benefit-risk assessments and the EtR Framework. Data from national vaccine administration data systems, vaccine effectiveness platforms, and vaccine safety surveillance were also critical to COVID-19 vaccine policy discussions and are described elsewhere in the supplement[27,101,118]. Rapid generation of evidence-based vaccine policy required access to a variety of data; investments in partnerships and data infrastructure allowed near-real-time data integration into vaccine recommendations.

12. Summary and conclusions

Over 675 million doses of COVID-19 vaccines have been administered in the United States, and over 80 % of the U.S. population has had at least 1 dose of a COVID-19 vaccine[119]. Over the course of the COVID-19 pandemic in the United States, over one million people died from COVID-19, and over six million were hospitalized[120]. It has been estimated that COVID-19 vaccines prevented more than 18 million additional hospitalizations and more than 3 million additional deaths due to COVID-19 in the United States [1]. ACIP had the critical task of rapidly and thoroughly reviewing emerging and evolving data on COVID-19 epidemiology and vaccines, as well as making comprehensive population-based recommendations for vaccine policy and considerations for implementation through a transparent and evidence-based framework. Data review and discussions regarding the frequency and timing of COVID-19 vaccines in future years are ongoing. Efforts for simplification of vaccine policy and enhancement of vaccine equity continue, and the goal of a ‘variant-proof’ next-generation COVID-19 vaccine remains. Safe and effective COVID-19 vaccines, recommended through transparent policy discussions with ACIP, remain the best tool we have to prevent serious illness, hospitalization and death from COVID-19.

Data Statement

All data presented are cited and publicly available by ACIP presentations and ACIP website.

This article does not contain research data.

Data availability

All data are already publicly available