Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Use of Inactivated Vero Cell Culture-derived Japanese Encephalitis Vaccine in Children

Inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [manufactured as IXIARO]) is the only JE vaccine licensed and available in the United States. JE-VC is manufactured by Intercell Biomedical (Livingston, United Kingdom) and distributed in the United States private market by Novartis Vaccines (Cambridge, Massachusetts). In March 2009, FDA licensed JE-VC for use in adults aged ≥17 years. ACIP recommendations for use of JE-VC in adults were approved in June 2009 and booster dose recommendations were approved in February 2011 [CDC 2010; CDC 2011]. There are no efficacy data for JE-VC. However, a JE virus 50% plaque reduction neutralization test (PRNT50) titer of ≥10 is an established immunologic correlate of protection [Markoff 2000; Hombach 2005]. JE-VC was licensed based on its ability to induce neutralizing antibodies and a non-inferiority comparison to a licensed inactivated mouse brain-derived JE vaccine (JE-MB [manufactured as JE-VAX]). Since JE-VC was licensed in 2009, >375,000 doses have been distributed in the United States for use in adults. In May 2013, FDA approved JE-VC for use in children aged 2 months through 16 years [FDA 2013]. The FDA-approved primary series for JE-VC is two intramuscular doses administered 28 days apart. For children aged 2 months through 2 years each dose is 0.25mL and for adults and children aged ≥3 years each dose is 0.5mL. The ACIP JE Vaccine Workgroup evaluated the evidence for use of JE-VC in children using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methods [Ahmed 2011]. The workgroup developed a policy question, identified outcomes of critical importance, performed a systematic review of the available data, and evaluated evidence of benefits, harms, values, and preferences for use of JE vaccine in U.S. children.

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) use among adults aged 19­64 years with an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant who previously received a 13-valent pneumococcal conjugate vaccine (PCV13)

On October 19, 2022, the U.S. Advisory Committee on Immunization Practices (ACIP) recommended the use of either a dose of 20-valent pneumococcal conjugate vaccine (PCV20) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) as previously recommended for adults who have received 13-valent pneumococcal conjugate vaccine (PCV13) with an incomplete vaccination status. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for evidence assessment and decision-making informed ACIP's deliberations regarding use of this vaccine.

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) use among adults aged ≥65 years who previously received a 13-valent pneumococcal conjugate vaccine (PCV13)

On October 19, 2022, the U.S. Advisory Committee on Immunization Practices (ACIP) recommended the use of either a dose of 20-valent pneumococcal conjugate vaccine (PCV20) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) as previously recommended for adults who have received 13-valent pneumococcal conjugate vaccine (PCV13) with an incomplete vaccination status. In addition, ACIP recommended shared clinical decision-making regarding administration of PCV20 for adults aged ≥65 years who completed their vaccine series with both PCV13 and PSPV23. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for evidence assessment and decision-making informed ACIP's deliberations regarding use of PCV20.

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) for children aged <2 years

On June 22, 2023, the CDC's Advisory Committee on Immunization Practices (ACIP) recommended use of 20-valent pneumococcal conjugate vaccine (PCV20 [Prevnar 20, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.]) as an option to 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) for: routine vaccination of all children aged 2­23 months; catch-up vaccination for healthy children aged 24­59 months who have not received age-appropriate doses; and children aged 24­71 months with certain underlying medical conditions at increased risk for pneumococcal disease* who have not received age-appropriate doses. In addition, recommendations were updated for children aged 2­18 years with any risk conditions. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP's deliberations regarding use of this vaccine. Underlying medical conditions include: cerebrospinal fluid leak; chronic heart disease; chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in immunocompromising conditions); chronic liver disease; chronic lung disease (including moderate persistent or severe persistent asthma); cochlear implant; diabetes mellitus; immunocompromising conditions (on maintenance dialysis or with nephrotic syndrome; congenital or acquired asplenia or splenic dysfunction; congenital or acquired immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; and sickle cell disease or other hemoglobinopathies).

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) for children aged 2 through 18 years with underlying medical conditions

On June 22, 2023, the CDC's Advisory Committee on Immunization Practices (ACIP) recommended use of 20-valent pneumococcal conjugate vaccine (PCV20 [Prevnar 20, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.]) as an option to 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) for: routine vaccination of all children aged 2­23 months; catch-up vaccination for healthy children aged 24­59 months who have not received age-appropriate doses; and children aged 24­71 months with certain underlying medical conditions at increased risk for pneumococcal disease* who have not received age-appropriate doses. In addition, recommendations were updated for children aged 2­18 years with any risk conditions. Indications for risk-based pneumococcal vaccine recommendations were expanded to include children with chronic kidney disease (even if not on maintenance dialysis or nephrotic syndrome), chronic liver disease, and moderate persistent or severe persistent asthma (regardless of high-dose oral corticosteroids use). A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP's deliberations regarding use of this vaccine. *Underlying medical conditions include: cerebrospinal fluid leak; chronic heart disease; chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in immunocompromising conditions); chronic liver disease; chronic lung disease (including moderate persistent or severe persistent asthma); cochlear implant; diabetes mellitus; immunocompromising conditions (on maintenance dialysis or with nephrotic syndrome; congenital or acquired asplenia or splenic dysfunction; congenital or acquired immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; and sickle cell disease or other hemoglobinopathies)

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Nirsevimab, Season 1

A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms of the long-acting monoclonal antibody nirsevimab, (Beyfortus, Sanofi and AstraZeneca) for prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI) in infants born during or entering their first RSV season was presented to the Advisory Committee on Immunization Practices (ACIP) on February 23, 2023. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty [1].

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Nirsevimab, Season 2

A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms for the long-acting monoclonal antibody nirsevimab, (Beyfortus, Sanofi and AstraZeneca) for prevention of respiratory syncytial virus (RSV))-associated lower respiratory tract infection (LRTI) in children <24 months who are at increased risk of severe disease entering their second RSV season was presented to the Advisory Committee on Immunization Practices (ACIP) on February 23, 2023. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Safety of Influenza Vaccines for Persons with Egg Allergy

Most of the influenza vaccines currently approved and available in the United States are produced by the propagation of influenza viruses in eggs (1-7). These vaccines therefore can contain small quantities of egg proteins. As of the 2022-23 influenza season, ACIP has recommended annual influenza vaccination for all persons aged 6 months and older with egg allergy, regardless of severity of previous allergic reactions to egg and with any licensed influenza vaccine that is otherwise appropriate for the recipient's age and health status (8). For those with a history of severe allergic reaction to egg (defined as any symptom other than hives), an additional recommendation has been made that such individuals be vaccinated in a medical setting, supervised by a provider who is able to recognize and manage a severe allergic reaction. This recommendation differs from those of the American Academy of Pediatrics, which since the 2016-17 influenza season has recommended that no measures beyond those recommended for any recipient of any vaccine are needed for persons with egg allergy (9). Such measures are also not recommended by the Joint Task Force of the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) (10). Additionally, vaccination providers are recommended to be prepared for the possibility of severe allergic reactions when administering any vaccine to any recipient (11). The current review was performed to assess whether the safety of influenza vaccines for persons with egg allergy favors routine vaccination of this population without additional measures, regardless of severity of previous allergic reactions to egg.

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): GSK RSVPreF3 Vaccine (AREXVY)

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for GSK Respiratory Syncytial Virus (RSV) PreF3 vaccine was presented to the Advisory Committee on Immunization Practices (ACIP) on June 21, 2023. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty. The policy questions were, "Should vaccination with GSK RSVPreF3 vaccine (120µg antigen + AS01E adjuvant, 1 dose administered intramuscularly [IM]), rather than no vaccine, be recommended in persons aged ≥65 years?" and "Should vaccination with GSK RSVPreF3 vaccine (120µg antigen + AS01E adjuvant, 1 dose IM), rather than no vaccine, be recommended in persons aged 60­64 years?" The benefits chosen by the ACIP RSV Vaccines Work Group (Work Group) as critical or important to policy decisions were prevention of RSV lower respiratory tract illness/disease (LRTI/LRTD) (critical), medically attended RSV LRTI/LRTD (critical), hospitalization for RSV respiratory illness (important), severe RSV respiratory illness requiring supplemental oxygen (O2) or other respiratory support (important), and death due to RSV respiratory illness (important). The harms chosen by the Work Group as critical or important to policy decisions were serious adverse events (critical), inflammatory neurologic events* (important) and reactogenicity grade ≥3 (important). A systematic review of evidence on the efficacy and safety of GSK RSVPreF3 vaccine among persons aged 60 years and older was conducted. The quality of evidence from one Phase 3 randomized controlled trial (RCT) and one Phase 1/2 RCT were assessed using the GRADE approach [2-4]. Efficacy findings were based on analyses of data collected during May 2021­March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants. A lower risk of RSV LRTD† was observed with vaccination compared to placebo (incident rate ratio [IRR] 0.254, 95% confidence interval [CI]: 0.165, 0.379, evidence certainty: moderate), corresponding to a vaccine efficacy of 74.6% (95% CI: 62.1%, 83.5%)§. A lower risk of medically attended RSV LRTD¶ was also observed (IRR 0.225; 95% CI: 0.110, 0.421; evidence certainty: moderate), corresponding to a vaccine efficacy of 77.5% (95% CI: 57.9%, 89.0%).** The trial was not powered to detect a lower risk of hospitalization for RSV respiratory illness or severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (for both outcomes IRR 0.236; 95% CI: 0.005, 2.112; evidence certainty: very low), corresponding to a vaccine efficacy for both outcomes of 76.4% (95% CI: -111%, 99.5%). No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients. In terms of harms, the pooled available data from the Phase 3 and Phase 1/2 RCTs indicated that serious adverse events (SAEs)†† were balanced between participants in the vaccine and placebo arms (risk ratio [RR] 1.019; 95% CI: 0.908, 1.145; evidence certainty: high). Reactogenicity grade ≥3§§ was associated with vaccination (RR 4.099; 95% CI: 1.989, 8.446; evidence certainty: high), with 3.8% of vaccine recipients and 0.9% of placebo recipients reporting any grade ≥3 local or systemic reactions following injection. No inflammatory neurologic events were observed within 42 days after injection in either placebo-controlled trial. However, inflammatory neurologic events were observed in other trials not included in the GRADE assessment due to lack of an unvaccinated comparator: one event of Guillain-Barré syndrome (GBS) reported within 42 days after vaccination in a recipient of the investigational vaccine in an open label trial without a placebo arm and two events of acute disseminated encephalomyelitis (ADEM) reported within 42 days after coadministration of the investigational vaccine with standard dose seasonal influenza vaccine in a coadministration study (for one of these ADEM cases the investigator revised the diagnosis to hypoglycemia and dementia in June of 2023).

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Pfizer RSVpreF Vaccine (ABRYSVO)

A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) review of the evidence for benefits and harms for Pfizer Respiratory Syncytial Virus (RSV) preF vaccine was presented to the Advisory Committee on Immunization Practices (ACIP) on June 21, 2023. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty [1]. The policy questions were, "Should vaccination with Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose administered intramuscularly [IM]), rather than no vaccine, be recommended in persons aged ≥65 years?" and "Should vaccination with Pfizer bivalent RSVpreF vaccine (120µg antigen, 1 dose IM), rather than no vaccine, be recommended in persons aged 60­64 years?" The benefits chosen by the ACIP RSV Vaccines Work Group (Work Group) as critical or important to policy decisions were prevention of RSV lower respiratory tract illness/disease (LRTI/LRTD) (critical), medically attended RSV LRTI/LRTD (critical), hospitalization for RSV respiratory illness (important), severe RSV respiratory illness requiring supplemental oxygen (O2) or other respiratory support (important), and death due to RSV respiratory illness (important). The harms chosen by the Work Group as critical or important to policy decisions were serious adverse events (critical), inflammatory neurologic events* (important) and reactogenicity grade ≥3 (important). A systematic review of evidence on the efficacy and safety of Pfizer RSVpreF vaccine among persons aged 60 years and older was conducted. The quality of evidence from one Phase 3 randomized controlled trial (RCT) and one Phase 1/2 RCT were assessed using the GRADE approach [2-4]. A lower risk of RSV LRTI† was observed with vaccination compared to placebo (incidence rate ratio [IRR] 0.156, 95% confidence interval [CI]: 0.048, 0.404, evidence certainty: moderate), corresponding to a vaccine efficacy of 84.4% (95% CI: 59.1%, 95.2%)§. This was observed over one complete RSV season (Season 1) and one partial second RSV season (Season 2). A lower risk of medically attended RSV LRTI¶ was also observed (IRR 0.191; 95% CI: 0.047, 0.563; evidence certainty: moderate), corresponding to a vaccine efficacy of 81.0% (95% CI: 43.5%, 95.2%)§. The trial was not powered to detect a lower risk of hospitalization for RSV respiratory illness (IRR 0.333; 95% CI: 0.006, 4.143; evidence certainty: very low) nor a lower risk for severe RSV respiratory illness requiring supplemental oxygen or other respiratory support** (IRR 0.000; 95% CI: 0.013, 78.33; evidence certainty: very low), corresponding to a vaccine efficacy of 66.7% (95% CI: -315%, 99.4%) and 0% (-7750%, 98.7%) for the outcomes, respectively. No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients. In terms of harms, the pooled available data from the Phase 3 and Phase 1/2 RCTs indicated that serious adverse events (SAEs)†† were balanced between the vaccine and placebo arms (risk ratio [RR] 1.041; 95% CI: 0.944, 1.148; evidence certainty: high). Reactogenicity grade ≥3§§ was similar between the vaccine and placebo arms of the trials (RR 1.43; 95% CI: 0.852, 2.385; evidence certainty: moderate), with 1.0% of vaccine recipients and 0.7% of placebo recipients reporting any grade ≥3 local or systemic reactions following injection. Three participants in the intervention group of the Phase 3 trial were reported to have inflammatory neurologic events within 42 days after vaccination (one case of Guillain-Barré syndrome [GBS], one case of Miller Fisher syndrome [a GBS variant], and one case of undifferentiated motor-sensory axonal polyneuropathy with worsening of pre-existing symptoms), compared with zero participants in the placebo group. No inflammatory neurologic events were reported in the phase 1/2 RCT.

GRADE: PCV15 use in children aged 2­18 years with certain underlying medical conditions that increase the risk of pneumococcal disease

On June 22, 2022, ACIP recommended use of 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) as an option for pneumococcal conjugate vaccination for persons aged <19 years according to currently recommended PCV13 dosing and schedules. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP's deliberations regarding use of this vaccine.

GRADE: 15-valent pneumococcal conjugate vaccine (PCV15) use in children aged <2 years

On June 22, 2022, ACIP recommended use of 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) as an option for pneumococcal conjugate vaccination for persons aged <19 years according to currently recommended PCV13 dosing and schedules. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP's deliberations regarding use of this vaccine.

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Lyophilized CVD 103-HgR Vaccine Among Children and Adolescents Aged 2­17 Years

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for use of lyophilized CVD 103-HgR vaccine (CVD 103-HgR) among children and adolescents aged 2­17 years was presented to the Advisory Committee for Immunization Practices (ACIP) on January 12, 2022. GRADE evidence type indicates the certainty of estimates from the available body of evidence, ranging from type 1 (high certainty) to type 4 (very low certainty).1 The policy question was "Should ACIP recommend lyophilized CVD 103-HgR vaccine for children and adolescents aged 2­17 years traveling to an area with active cholera transmission?" (Table 1). The potential benefits pre-specified by the ACIP Cholera Vaccine Work Group were moderate to severe cholera diarrhea (critical) and cholera diarrhea of any severity (critical). The two pre-specified harms were serious adverse events (SAEs) (critical) and non-serious adverse events (important) (Tables 1 and 2). The work group conducted a systematic review of evidence on the benefits and harms of CVD 103-HgR among children and adolescents aged 2­17 years old. Studies identified were assessed using a modified GRADE approach.1 Regarding benefits, no studies of CVD 103-HgR in children and adolescents aged 2­17 years directly assessed vaccine efficacy or effectiveness against cholera diarrhea. The available data from randomized control trials (RCTs) demonstrated that, compared with placebo, vaccination was associated with a higher risk of serum vibriocidal antibody (SVA) seroconversion (pooled relative risk [RR]: 65.99, 95% CI: 9.43­461.69; pooled absolute risk [AR]: 97,000 more per 100,000, 95% CI: 12,582 more to 100,000 more). The evidence certainty was downgraded for serious imprecision, and the final level of certainty was type 2 (moderate) for both benefits. Regarding harms, the available data from RCTs demonstrated the vaccine and placebo arms had a similar risk of serious adverse events (pooled RR: 0.16, 95% CI 0.01­2.53; pooled AR: 1,120 fewer per 100,000, 95% CI: 1,320 fewer to 2,040 more); no serious adverse events were judged to be related to the vaccine among 468 recipients aged 2­17 years within 6 months of vaccination. The risk of non-serious adverse events was similar between the vaccine and placebo groups (pooled RR: 1.09, 95% CI 0.86­1.38; pooled AR: 4,560 more per 100,000, 95% CI: 7,093 fewer to 19,253 more). For both harms, the evidence certainty was downgraded for very serious imprecision, and the final certainty was type 3 (low).

GRADE: Higher Dose and Adjuvanted Influenza Vaccines for Persons Aged ≥65 Years

Estimated rates of influenza-associated hospitalization and death are generally highest among individuals 65 years of age and older (1-4), an age group for whom influenza vaccine effectiveness is often lower relative to younger populations (5, 6). Two inactivated influenza vaccines approved in the U.S. for persons aged ≥65 years have features intended to promote a better immune response for this age group. These include a high-dose inactivated influenza vaccine containing four times the antigen dosage per virus compared with standard dose inactivated vaccines (approved as a trivalent formulation [HD-IIV3] in 2009 and a quadrivalent formulation [HD-IIV4] in 2019), and an inactivated vaccine containing the adjuvant agent MF59 (approved as a trivalent formulation [aIIV3] in 2015 and a quadrivalent formulation [aIIV4] in 2020). These two vaccines, as well as a recombinant influenza vaccine containing three times the antigen dosage per virus compared with SD-IIVs (initially licensed as a trivalent formulation [RIV3] in 2013 and as a quadrivalent [RIV4] in 2016 and approved for ages ≥18 years), have been evaluated for relative efficacy and effectiveness compared with standard dose unadjuvanted inactivated influenza vaccines (SD-IIVs) among older adults (7-9). This assessment sought to review the available published evidence for relative efficacy, effectiveness, and safety of HD-IIV, aIIV, and RIV to support ACIP discussion of whether any one or more of these three vaccines should be preferentially recommended over other age-appropriate influenza vaccines (unadjuvanted SD-IIVs) for persons ages 65 years and older.

Grading of recommendations, assessment, development, and evaluation (GRADE): Novavax COVID-19 vaccine

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for Novavax coronavirus disease 2019 (COVID-19) vaccine was presented to the Advisory Committee on Immunization Practices (ACIP) on July 19, 2022. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty) [1]. The policy question was, "Should vaccination with Novavax COVID-19 vaccine be recommended for persons 18 years of age and older during an Emergency Use Authorization?" The potential benefits pre-specified by the ACIP COVID-19 Vaccines Work Group were prevention of symptomatic laboratory-confirmed COVID-19 (critical), hospitalization due to COVID-19 (critical), death due to COVID-19 (important), and asymptomatic SARS-CoV-2 infection (important). The two pre-specified harms were serious adverse events (critical) and reactogenicity grade ≥3 (important). A systematic review of evidence on the efficacy and safety of a two-dose regimen of Novavax COVID-19 vaccine among persons aged 18 years and older was conducted. The quality of evidence from one Phase III randomized controlled trial was assessed using a modified GRADE approach [2-3]. A lower risk of symptomatic COVID-19 was observed with vaccination compared to placebo (relative risk [RR] 0.10, 95% confidence interval [CI]: 0.06, 0.18, evidence type 1), corresponding to a vaccine efficacy of 89.6% (95% CI: 82.4%, 93.8%). This was observed with a median follow-up of 2.5 months, during a period of Alpha variant predominance. The vaccine was also associated with a lower risk of severe illness due to COVID-19 (RR 0.00; 95% CI: 0.00, 1.00; evidence type 3), corresponding to a vaccine efficacy of 100% (95% CI: 0%, 100%). The measure of severe COVID-19 was used as surrogate for the GRADE outcome of hospitalization due to COVID-19. No hospitalizations or deaths due to COVID-19 were identified among vaccine recipients or placebo recipients in the per-protocol population.* In terms of harms, the available data indicated that serious adverse events were balanced between the vaccine and placebo arms (RR 0.92; 95% CI: 0.73, 1.16; evidence type 1). Reactogenicity grade ≥3 was associated with vaccination (RR 4.11; 95% CI: 3.70, 4.57; evidence type 1), 16.3% of vaccine recipients and 4% of placebo recipients reported any grade ≥3 local or systemic reactions following either dose 1 or dose 2.

ACIP evidence to recommendations for use of Novavax COVID-19 vaccine, adjuvanted in adults ages 18 years and older under an emergency use authorization

The emergence of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), in late 2019 has led to a global pandemic with dramatic societal and economic impact on individual persons and communities. In the United States, more than 89 million cases and more than 1 million COVID-19-associated deaths have been reported as of July 14, 2022. Persons of all ages are at risk for infection and severe disease. However, the risk for severe illness from COVID-19 is higher in people aged ≥65 years, those living in long-term care facilities, and those with chronic medical conditions. Additionally, there is a disproportionate burden of COVID-19 infections and deaths among racial and ethnic minority communities. Non-Hispanic Black, Hispanic/Latino (Hispanic) and American Indian/Alaska Native persons have experienced higher rates of disease, hospitalization and death compared with non-Hispanic White persons. This is likely related to inequities in social determinants of health that put racial and ethnic minority groups at increased risk for COVID-19, including overrepresentation among essential workers who have higher risk of exposure to COVID-19, lower incomes, reduced access to healthcare, or higher rates of comorbid conditions. In the United States, the first vaccines to prevent COVID-19 received Food and Drug Administration (FDA) Emergency Use Authorizations (EUA): Pfizer-BioNTech on December 11, 2020, for persons aged 16 years and older, Moderna on December 18, 2020, for adults aged 18 years and older, and Janssen on February 27, 2021, for adults aged 18 years and older. On July 13, 2022, the FDA issued an EUA for the Novavax COVID-19 vaccine, Adjuvanted for the prevention of COVID-19 in persons ages 18 years and older. Additional background information supporting the interim ACIP recommendation on the use of Novavax COVID-19 vaccine can be found in the relevant publication of the recommendation referenced on the ACIP website.

Grading of recommendations, assessment, development, and evaluation (GRADE): Moderna COVID-19 vaccine for children aged 6­11 years

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for Moderna coronavirus disease 2019 (COVID-19) vaccine for children aged 6­11 years was presented to the Advisory Committee for Immunization Practices (ACIP) on June 23, 2022. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty) [1]. The policy question was, "Should vaccination with Moderna COVID-19 vaccine (2 doses, 50 µg) be recommended for children 6­11 years of age during an Emergency Use Authorization?" The potential benefits pre-specified by the ACIP COVID-19 Vaccines Work Group included prevention of symptomatic laboratory-confirmed COVID-19 (critical), hospitalization due to COVID-19 (important), multisystem inflammatory syndrome in children (MIS-C) (important), and asymptomatic SARS-CoV-2 infection (important). The two pre-specified harms were serious adverse events (SAEs) (critical) and reactogenicity grade ≥3 (important). A systematic review of evidence on the efficacy and safety of a two-dose regimen of Moderna COVID-19 vaccine among children aged 6­11 years was conducted. The quality of evidence from one Phase II/III randomized controlled trial was assessed using a modified GRADE approach [2]. Symptomatic COVID-19 was less common among the vaccine group compared with the placebo group (RR: 0.19; 95% CI: 0.05, 0.81; evidence type 2). A non-inferior geometric mean ratio (GMR) for antibodies in the 6­11-year-olds was observed with vaccination compared to the 18­25-year-olds (GMR 1.2, 95% confidence interval [CI]: 1.1, 1.4; evidence type 2). A lower risk of asymptomatic SARS-CoV-2 infection also seen in the vaccine group compared with the placebo group (Relative Risk [RR]: 0.29; 95% CI: 0.12, 0.71; evidence type 3). The available data indicated that SAEs were balanced between the vaccine and placebo arms, but certainty in the estimate was very low (RR 0.99; 95% CI: 0.20, 4.91; evidence type 4); none of these SAEs were assessed by the Food and Drug Administration (FDA) as related to study intervention. Reactogenicity grade ≥3 was associated with vaccination (RR 5.2; 95% CI: 3.6, 7.3; evidence type 1). About 17% of vaccine recipients and 3% of placebo recipients reported any grade ≥3 local or systemic reactions following either dose 1 or dose 2.

Grading of recommendations, assessment, development, and evaluation (GRADE): Moderna COVID-19 vaccine for persons aged 12-17 years

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for Moderna coronavirus disease 2019 (COVID-19) vaccine for persons aged 12-17 years was presented to the Advisory Committee for Immunization Practices (ACIP) on June 23, 2022. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty) [1]. The policy question was, "Should vaccination with Moderna COVID-19 vaccine (2 doses, 100 µg) be recommended for persons 12-17 years of age during an Emergency Use Authorization?" The potential benefits pre-specified by the ACIP COVID-19 Vaccines Work Group included prevention of symptomatic laboratory-confirmed COVID-19 (critical), hospitalization due to COVID-19 (important), multisystem inflammatory syndrome in children (MIS-C) (important), and asymptomatic SARS-CoV-2 infection (important). The two pre-specified harms were serious adverse events (SAEs) (critical) and reactogenicity grade ≥3 (important). A systematic review of evidence on the efficacy and safety of a two-dose regimen of Moderna COVID-19 vaccine among persons aged 12-17 years was conducted. The quality of evidence from one Phase II/III randomized controlled trial was assessed using a modified GRADE approach. A lower risk of symptomatic COVID-19 was observed among the vaccine group compared with the placebo group (Relative risk [RR]: 0.11; 95% Confidence Interval [CI]: 0.02, 0.50; evidence type 2). Immunobridging data were also assessed in support of efficacy. Among adolescents ages 12 ­ 17 years, the immune response to vaccine was non-inferior to that observed in adults ages 18-25 years ( GMR: 1.1; 95% CI: 0.9, 1.2; evidence type 2). Additionally, a lower risk of asymptomatic SARS-CoV-2 infection was observed among the vaccine group compared with the placebo group, though the confidence interval was wide and crossed the null (RR: 0.61 (0.24, 1.54); evidence type 3). The available data indicated that SAEs were more common in vaccine recipients, but certainty in the estimate was very low (RR 1.50; 95% CI: 0.30, 7.40; evidence type 4), and none of these SAEs were assessed by the Food and Drug Administration (FDA) as related to study intervention. Reactogenicity grade ≥3 was associated with vaccination (RR 5.23; 95% CI: 4.05, 6.76; evidence type 1). About 25% of vaccine recipients and 5% of placebo recipients reported any grade ≥3 local or systemic reactions following either dose 1 or dose 2.

Grading of recommendations, assessment, development, and evaluation (GRADE): Moderna COVID-19 vaccine for children aged 6 months­5 years

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for Moderna coronavirus disease 2019 (COVID-19) vaccine for children aged 6 months­-­­5 years was presented to the Advisory Committee for Immunization Practices (ACIP) on June 18, 2022. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty) [1]. The policy question was, "Should vaccination with Moderna COVID-19 vaccine (2 doses, 25 µg) be recommended for children 6 months-5 years of age during an Emergency Use Authorization?" The potential benefits pre-specified by the ACIP COVID-19 Vaccines Work Group included prevention of symptomatic laboratory-confirmed COVID-19 (critical), hospitalization due to COVID-19 (important), multisystem inflammatory syndrome in children (MIS-C) (important), and asymptomatic SARS-CoV-2 infection (important). The two pre-specified harms were serious adverse events (SAEs) (critical) and reactogenicity grade ≥3 (important). A systematic review of evidence on the efficacy and safety of a two-dose regimen of Moderna COVID-19 vaccine among children aged 6 months­5 years was conducted. The quality of evidence from one Phase II/III randomized controlled trial was assessed using a modified GRADE approach [2]. A lower risk of symptomatic COVID-19 was observed with vaccination compared with placebo (relative risk [RR]: 0.62; 95% confidence interval [CI]: 0.49, 0.79, evidence type 1). Immunobridging was also assessed. In both age groups, 6­23 months and 2­5 years, the immune response to vaccine was non-inferior to that observed in adults ages 18-25 years (6­23 months GMR: 1.28; 95% CI: 1.12, 1.47; 2­5 years GMR: 1.01; 95% CI: 0.88, 1.17; evidence type 2). There was also a lower risk of asymptomatic SARS-CoV-2 infection seen in the vaccine group compared with the placebo group, however the confidence interval crossed the line of no effect (RR: 0.84; 95% CI: 0.60,1.19; evidence type 3). The available data indicated that SAEs were more common in vaccine recipients, but certainty in the estimate was very low (RR 2.67; 95% CI: 0.80, 8.84; evidence type 4). Two serious adverse events in one participant were determined by the Food and Drug Administration (FDA) as potentially related to the vaccination. No specific safety concerns were identified among vaccine recipients aged 6 months­5 years. Reactogenicity grade ≥3 was associated with vaccination (RR 1.87; 95% CI: 1.44, 2.42); evidence type 1). About 7.7% of vaccine recipients and 4.4% of placebo recipients reported any grade ≥3 local or systemic reactions following either dose 1 or dose 2.

Grading of recommendations, assessment, development, and evaluation (GRADE): Pfizer-BioNTech COVID-19 vaccine for children aged 6 months-4 Years

Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine for children aged 6 months­­­­4 years was presented to the Advisory Committee for Immunization Practices (ACIP) on June 18, 2022. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty) [1]. The policy question was, "Should vaccination with Pfizer-BioNTech COVID-19 vaccine (3 doses, 3 µg) be recommended for children 6 months­4 years of age during an Emergency Use Authorization?" The potential benefits pre-specified by the ACIP COVID-19 Vaccines Work Group included prevention of symptomatic laboratory-confirmed COVID-19 (critical), hospitalization due to COVID-19 (important), multisystem inflammatory syndrome in children (MIS-C) (important), and asymptomatic SARS-CoV-2 infection (important). The two pre-specified harms were serious adverse events (SAEs) (critical) and reactogenicity grade ≥3 (important). A systematic review of evidence on the efficacy and safety of a three-dose regimen of Pfizer-BioNTech COVID-19 vaccine among children aged 6 months­4 years was conducted. The quality of evidence from one Phase II/III randomized controlled trial was assessed using a modified GRADE approach [2]. A lower risk of symptomatic COVID-19 was observed with vaccination compared with placebo, but certainty in the estimate was very low (relative risk [RR]: 0.20; 95% confidence interval [CI]: 0.05, 0.77, evidence type 4). Immunobridging was also assessed in support of efficacy. In both age groups, 6­23 months and 2­4 years, the immune response to vaccine was non-inferior to that observed in young adults ages 16-25 years (6­23 months: GMR: 1.19; 95% CI: 1.00, 1.43; 2­4 years: GMR: 1.30; 95% CI: 1.13, 1.50; evidence type 2). The available data indicated that SAEs were balanced comparing vaccine and placebo recipients, but certainty in the estimate was low (RR 0.66; 95% CI: 0.38, 1.15; evidence type 4). One vaccine recipient had two SAEs which were considered potentially related by the investigator and FDA. FDA noted that the events were also consistent with viral myositis. Reactogenicity grade ≥3 was slightly higher in the vaccine group, but the confidence interval crossed the null (RR 1.20; 95% CI: 0.88, 1.64); evidence type 2). About 4.3% of vaccine recipients and 3.6% of placebo recipients reported any grade ≥3 local or systemic reactions following dose 1, dose 2, or dose 3.