The impact of vaccination and outpatient treatment on the economic burden of Covid-19 in the United States omicron era: a systematic literature review

Abstract Aims To identify and synthesize evidence regarding how coronavirus disease 2019 (COVID-19) interventions, including vaccines and outpatient treatments, have impacted healthcare resource use (HCRU) and costs in the United States (US) during the Omicron era. Materials and methods A systematic literature review (SLR) was performed to identify articles published between 1 January 2021 and 10 March 2023 that assessed the impact of vaccination and outpatient treatment on costs and HCRU outcomes associated with COVID-19. Screening was performed by two independent researchers using predefined inclusion/exclusion criteria. Results Fifty-eight unique studies were included in the SLR, of which all reported HCRU outcomes, and one reported costs. Overall, there was a significant reduction in the risk of COVID-19-related hospitalization for patients who received an original monovalent primary series vaccine plus booster dose vs. no vaccination. Moreover, receipt of a booster vaccine was associated with a lower risk of hospitalization vs. primary series vaccination. Evidence also indicated a significantly reduced risk of hospitalizations among recipients of nirmatrelvir/ritonavir (NMV/r), remdesivir, sotrovimab, and molnupiravir compared to non-recipients. Treated and/or vaccinated patients also experienced reductions in intensive care unit (ICU) admissions, length of stay, and emergency department (ED)/urgent care clinic encounters. Limitations The identified studies may not represent unique patient populations as many utilized the same regional/national data sources. Synthesis of the evidence was also limited by differences in populations, outcome definitions, and varying duration of follow-up across studies. Additionally, significant gaps, including HCRU associated with long COVID and various high-risk populations and cost data, were observed. Conclusions Despite evidence gaps, findings from the SLR highlight the significant positive impact that vaccination and outpatient treatment have had on HCRU in the US, including periods of Omicron predominance. Continued research is needed to inform clinical and policy decision-making in the US as COVID-19 continues to evolve as an endemic disease.


Introduction
The coronavirus (COVID-19) pandemic has caused more than 6.2 million hospitalizations and more than 1.1 million deaths in the United States (US) as of 24 August 2023 1 .COVID-19 was the fourth leading cause of death in the US in 2022 after heart disease, cancer, and unintentional injury 2 , and weekly new hospital admissions due to COVID-19 in the US remained among the highest compared to other countries globally as of 10 August 2023 3 .
The pandemic has resulted in a vast economic burden for both adults and children, particularly in patients with severe COVID-19 who require hospitalization, intensive care unit (ICU) admission, and mechanical ventilation [4][5][6] .Long COVID (also known as post-COVID conditions [PCC]), which can continue for months after initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been reported to impact approximately 15% of patients 7 .Long COVID is also associated with considerable economic burden as a result of outpatient visits and unemployment [7][8][9][10] .Furthermore, the redirection of healthcare resources towards COVID-19 has delayed healthcare for patients with other conditions such as cancer, communicable diseases, and mental disorders 11 .
Many studies have been published on the costs and healthcare resource utilization (HCRU) associated with COVID-19 in the US early on in the pandemic during 2020 and 2021 when the Alpha and Delta variants were predominant 4,9,[12][13][14][15] .However, evidence gaps remain in terms of more recent data on costs and HCRU associated with the Omicron variant 16 .Understanding the costs and HCRU during the Omicron predominant era (February 2022 through the present 16,17 ) is also complicated by multiple variables such as vaccine uptake (including of the updated bivalent vaccines), heterogeneity in the level and duration of protection elicited by vaccination or prior infection, and the availability and uptake of anti-SARS-CoV-2 treatments.
Although COVID-19 is no longer considered a public health emergency in the US, responding to the spread of SARS-CoV-2 remains a public health priority for the Department of Health and Human Services 18 .The World Health Organization has also emphasized the importance of continuing to limit SARS-CoV-2 transmission and treating patients with COVID-19 to reduce mortality and morbidity 19 .Quantifying the ongoing economic burden of COVID-19 and understanding the impact of vaccines and treatments can help inform policy decisions aimed at ensuring efficient operation of healthcare systems and uptake of medical countermeasures or interventions for COVID-19 management.The aim of this systematic literature review (SLR) was to identify and synthesize the evidence regarding how COVID-19 interventions, including vaccines and outpatient treatments, have influenced the economic burden (in terms of HCRU and costs) of COVID-19 in the US during the Omicron era.

Methods
An SLR was conducted following the standards set out in the Cochrane Handbook for Systematic Reviews of Interventions and the Centre for Review and Dissemination (CRD) Guidance developed by the University of York 20 .The protocol for the review was registered on the PROSPERO International prospective register of systematic reviews database (registration number: CRD42022370145).

Identification and Selection of studies
Structured search strategies were developed and executed in Embase, MEDLINE (and MEDLINE In-progress), and EconLit via OvidSP.The searches included free-text terms and controlled vocabulary terms for COVID-19, outcomes and study designs of interest, and US geographies (Table S1).The searches were run on 10 March 2023 and included studies published since 1 January 2021.Studies were not limited by language.Preprint articles were excluded if they were not published prior to the development of this manuscript (i.e. 10 July 2023).Citations and corresponding data for preprint articles captured by the SLR were updated to reflect the accepted peer-reviewed articles prior to development of this manuscript.Supplemental searching of the bibliography lists of relevant SLRs/meta-analyses identified by the database searches were also carried out to ensure that no relevant articles were missed.
Predefined inclusion/exclusion criteria following population, intervention, comparator, outcomes, and study (PICOS) design criteria (Table 1) were used to evaluate all records identified from the searches.Given the interest in understanding how the economic outcomes may be impacted by variant, age group, level of risk for severe COVID-19 outcomes, and vaccination/treatment status, subgroup data based on these factors were captured by the SLR.Two researchers independently performed all title/abstract and full-text screening, with any discrepancies resolved by a third, independent researcher.

Data extraction and synthesis
Data of interest were extracted by a single, independent researcher, and fully validated by a second researcher to ensure quality and accuracy.Any disagreements were resolved by conferring with a third reviewer.Data extraction templates were developed in Microsoft Excel V R to capture and present key evidence from each study identified for inclusion.During data extraction, related publications and data sources were linked via reference identification numbers to ensure that overlapping data were identified and reported appropriately.
The results were summarized using narrative synthesis and forest plots for reported vaccine effectiveness (VE) or treatment effectiveness against COVID-19 hospitalization.When VE (or treatment effectiveness) was not reported, reported hazard ratios (HRs) or rate ratios (RRs) were used to calculate VE using the following formula: VE ¼ (1 -R) � 100, where R could be a HR or RR.Given the variability of the data identified by the SLR, no quantitative synthesis (i.e.meta-analysis) of the data was feasible.

Summary of included studies
The study selection process is summarized in Figure 1.A total of 2,693 articles, published between 1 January 2021 and 10 March 2023, were identified by the database searches.Following removal of duplicates and title/abstract screening, 84 articles were screened at the full text level and 58 studies met the PICOS criteria for inclusion in the SLR, representing over 126 million patients.All included studies reported HCRU outcomes and one study reported cost data.

Study characteristics
The majority of included studies were retrospective cohort studies (n ¼ 43; 74.1%); there were also six prospective cohort studies (10.3%), seven retrospective case-control studies (12.1%), and two cross-sectional studies (3.4%).HCRU data were obtained from hospital (n ¼ 17; 29.3%), regional (n ¼ 17; 29.3%), and national (n ¼ 24; 41.4%) databases.Most studies were multicenter (n ¼ 53; 91.4%), with the most common data sources being the US Department of Veterans Affairs healthcare system records (n ¼ 10; 17.2%), electronic health records for Kaiser Permanente members in Southern California (n ¼ 6; 10.3%), and the Centers for Disease Control and Prevention (CDC) Surveillance Networks (COVID-NET and Overcoming COVID; n ¼ 3; 5.2%).Data collection was predominantly conducted in inpatient settings (n ¼ 54; 93.1%), while four studies included outpatient encounters (6.9%).The most common reported duration of follow-up was 30 days post-confirmed infection (n ¼ 7), with the shortest duration of follow-up reported being >28 days and the longest, 285.5 days post-infection.Over half of the included studies did not report follow-up duration (n ¼ 38; 65.5%), and only one study assessed reinfection rates (90 days after initial infection, or 45 to 89 days after a symptomatic second episode).
The most common interventions compared within the included studies were primary series vaccination vs. no BNT162b2 (Pfizer Inc. and BioNTech) was the most frequently assessed vaccine and nirmatrelvir/ritonavir (NMV/r) (Pfizer Inc.) was the most frequently assessed antiviral treatment.All studies assessing outcomes related to outpatient treatments were conducted during periods of Omicron variant emergence and/or predominance, while only a small portion of vaccine studies were conducted solely during the Omicron era (n ¼ 7).Many of the vaccine studies had study periods that spanned Omicron variant emergence and/or predominance (n ¼ 18), but few reported outcomes of interest stratified by variant including Omicron (n ¼ 8). Figure 2 presents an overview of intervention assessed characteristics by study period.

Population characteristics
The characteristics of all studies are summarized in Table S2.
Most studies assessing vaccines focused on the adult population aged �18 years (n ¼ 29), of which two studies included adults age �50 years.Eleven studies included mixed age populations (i.e.age <18 and �18 years) and six focused only on children (age �18 years).Most vaccine studies reported high-risk characteristics among patients at baseline (n ¼ 26), which were highly variable.Forty studies confirmed SARS-CoV-2 detection with a nucleic acid amplification or antigen test while six studies did not specify methods for detecting SARS-CoV-2.
Most studies assessing outpatient treatments focused on adult populations (n ¼ 9; two studies including age �50 and �65 years).The remaining three studies included

Impact of booster vaccination
All booster studies were conducted during periods of Omicron and/or Delta predominance and assessed the original monovalent vaccines.Studies evaluated the VE of a booster dose (eight studies) or a primary series without a booster dose (12 studies), and the most commonly reported outcome was COVID-19-related hospitalization (Figure 3).

Booster compared to no vaccination
Among the eight studies that assessed the impact of the original monovalent booster vaccination compared with no vaccination, five studies were conducted in adults, three were conducted in mixed populations (all �12 years), and two were conducted in children (aged 6 to 17 years).Overall, these studies found a significant reduction in the risk of COVID-related hospitalization for patients who received an original monovalent primary series plus booster dose compared with no vaccination.One study conducted in California in mixed age populations estimated the risk of COVID-related hospitalization in unvaccinated individuals to be more than eight times greater than that of individuals who had received a booster dose (of any vaccine type) during periods of Delta and Omicron predominance (adjusted hazard ratio [aHR] 8.34 [95% confidence interval (CI): 7.25, 9.69]) 21 .Across other studies reporting the risk of hospitalization, the VE of a booster compared with no vaccination ranged from 63% (95% CI: 60%, 65%) to 94% (95% CI: 92%, 95%) (Figure 3) 22,23 .
The VE range for those who received a booster compared to no vaccination showed some correlation with SARS-CoV-2 variant.Hospitalization risk was lower during Omicron predominance compared with Delta predominance (Figure 3).Despite this reduction in VE associated with Omicron, unvaccinated individuals were reported in one study to have 10 to 11 times higher risk of Omicron-related hospitalization (January to April 2022) compared with individuals who had received a booster dose 24 .
The reduction in risk for severe COVID-19 following booster vaccination was reflected not only in hospitalization rates but also in the requirements for ICU admission, oxygen support, and invasive mechanical ventilation (IMV) 21 .During the period January 2021 through April 2022, 21.7% of unvaccinated adults infected with SARS-CoV-2 (1,961/8,575) required admission to an ICU, compared with 19.5% of adults (505/2,552) who had been vaccinated with a primary series with or without a booster dose (p ¼ 0.13) 24 .In a second study, unvaccinated individuals were at greater risk of needing low-flow oxygen support (aHR 5.68 [95% CI: 4.19, 7.69]), high-flow oxygen support (aHR 5.39 [95% CI: 3.45, 8.4]) or IMV (aHR 5.51 [95% CI: 2.44, 12.4]) during the Delta predominant period compared with booster dose recipients 21 .Overall, Omicron infection was associated with a lower risk of severe outcomes, with fewer patients requiring low-flow or high-flow oxygen support, or IMV during the Omicron vs. Delta predominant period (low-flow oxygen: 1.6% vs. 6.4%;high-flow oxygen: 0.6% vs. 2.8%; IMV: 0.1% vs. 0.7%) 21   � Effectiveness is described as reported or when not reported, was calculated from the reported hazard ratios or rate ratios using the following formula: Effectiveness ¼ (1 -R) � 100, where R could be a hazard ratio or rate ratio.Abbreviations.CI, confidence interval; mRNA, messenger ribonucleic acid; NMV/r, nirmatrelvir/Ritonavir; NR, not reported; Vx, vaccine.
Data on VE among children and adolescents were available in two of the studies identified in the SLR.Using an age-matched unvaccinated population as a reference, one study estimated the VE of a booster dose in preventing emergency department (ED)/urgent care visits among 16-to 17-year-olds to be 86% (95% CI: 73%, 95%) 25 .A second study estimated that VE in preventing ED or urgent care encounters related to acute respiratory failure caused by Omicron was 87% (95% CI: 72%, 94%) among 12-to 17-year-olds who had received a booster dose a median of 19 days earlier 26 .

Booster compared to primary series
The VE of a booster dose compared with primary series alone in preventing hospitalizations was evaluated in 12 studies (seven studies in adults, three studies with mixed populations, and two studies in elderly populations [�70 years old]).Overall, receipt of a booster vaccine was associated with a lower risk of hospitalization compared to receipt of only the primary series (Figure 3) 21,27 .A study conducted between January and April 2022 found that individuals who received an original monovalent primary series but no booster dose were up to three times more likely to be hospitalized with COVID-19 compared with individuals who received a booster dose 24 .
The VE of booster vaccination relative to an original monovalent primary series vaccination alone in the prevention of COVID-19-related hospitalization was estimated to range from 42% (95% CI: 33%, 49%) among individuals aged 0 to >80 years, to 81% (95% CI: 80%, 82%) in a study of individuals aged �65 years 21,28 .Despite this range, no obvious trends were observed according to variant or vaccine type (Figure 3).A study of 18.9 million adults found no significant differences in VE across various age groups or when comparing various combinations of primary and booster vaccines 28,29 .

Impact of primary vaccination
Thirty-eight studies reported outcomes of interest for primary series vaccines, spanning periods of Alpha, Delta, and/or Omicron predominance.
Primary series vaccination not only provided a reduction in hospitalization risk, but also reduced the risk of ICU admission and the IMV requirement, compared with no vaccination 22,24,34 .A study of adults hospitalized with COVID-19 in the US between April 2021 and January 2022, found the length of hospital stay to be significantly greater among unvaccinated vs. vaccinated patients (8.92 [±9.80] days vs. 6.47 [±4.76] days; p ¼ 0.03) 39 .Unvaccinated patients were also more likely to require ICU admission (p ¼ 0.006) and IMV use (p ¼ 0.0004) than vaccinated patients, and the mean duration of IMV was significantly longer among the unvaccinated compared with vaccinated patients (17.81 [±14.00]days vs. 3.01 [±2.75] days; p ¼ 0.003) 39 .Unadjusted hospitalization data showed that costs were nominally higher for the unvaccinated vs. vaccinated group ($191,146 [± $328,233] vs. $119, 630 [± $78,833]; p ¼ 0.006), with the cost of hospitalization per day being significantly higher in the former ($29,245 vs. $13,845; p < 0.0001) 39 .Correspondingly, following an adjustment for comorbidities and age, hospitalization costs were significantly lower for vaccinated compared with unvaccinated individuals (D 26%, p ¼ 0.004) 39 .
Primary series vaccination was also associated with reduction in HCRU among the pediatric population.In one study of individuals aged five through 17 years, conducted between April 2021 and January 2022, 71.6% of ED or urgent care encounters were accounted for by unvaccinated individuals (n ¼ 28,084/39,217), while 19.9% (n ¼ 7,821/39,217) and 8.3% (n ¼ 3,238/39,217) were accounted for by individuals who had received a second vaccine dose 14 to 149 days or �150 days earlier, respectively 25 .In a multicenter study of individuals aged 12 through 18 years, across 23 US states, ICU admissions and IMV requirements occurred in 42% (178/427) and 11% (48/425) of unvaccinated individuals, respectively, compared with 11.1% (n ¼ 2/18) and 5.6% (n ¼ 1/18) of vaccinated individuals, respectively 40 .A third study of individuals five to 15 years conducted between July 2021 and February 2022 found unvaccinated individuals missed a mean average of 26.2 h of school (standard error 17.5 h) as a result of COVID-19, approximately 11 h more than that missed by vaccinated individuals (OR 11.1 [95% CI: 4.6, 17.6]; p ¼ 0.01) 41 .The number of days spent sick in bed with COVID-19 was also greater among unvaccinated vs. vaccinated individuals (p ¼ 0.016).Despite this, the proportion of pediatric patients who sought medical care due to COVID-19 was not significantly different between the unvaccinated and vaccinated population (p ¼ 0.949) 41 .
The odds of hospitalization or ED visits within 29 days from symptom onset were lower in patients treated with remdesivir (OR: 0.41 [95% CI: 0.17,0.95])and sotrovimab (OR: 0.28 [95% CI: 0.11, 0.71]) than in patients without treatment between 27 December 2021 and 4 February 2022 44 .Sotrovimab also reduced the risk of 30-day hospitalization by 55% among high-risk patients diagnosed with COVID-19 between 1 September 2021 and 30 April 2022, compared to no monoclonal antibody treatment 45 .While was not evaluated separately in any of the studies identified in the SLR, one study conducted in adults aged �65 years between 1 January and 6 February 2022 reported reduced odds of hospitalization or death in patients treated with molnupiravir or NMV/r compared to untreated patients 46 .However, bebtelovimab did not significantly decrease the risk of 30-day all-cause hospitalization and/or mortality in high-risk patients infected with Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) compared with no treatment 49 .
Age �50 years is the strongest risk factor for severe COVID-19 outcomes, including hospitalization and death, based on February 2020 to July 2022 data from the US National Center for Health Statistics 50 .Patients who were unvaccinated or received fewer than the recommended number of vaccinations are also at higher risk of severe COVID-19 outcomes 50 .Results from two studies found patients receiving treatment for COVID-19 were more likely to be older than untreated patients 45,51 .Between 1 September 2021 and 30 April 2022, the median age of patients treated with sotrovimab was 55 years compared to 48 years for patients not treated with a monoclonal antibody (p < 0.0001) 45 .Similarly, patients treated with NMV/r, molnupiravir, remdesivir, or sotrovimab between 1 January and 28 February 2022 were more likely to be older (65 through 74 and �65 years vs. 50 through 64 years) than untreated patients 51 .Patients aged 50 through 64 years were also more likely to receive treatment than patients aged 18 through 49 years 51 .Among high-risk patients, NMV/r reduced the risk of hospitalization in patients aged 18 through 49 years (aHR 0.59 [95% CI: 0.48, 0.71]), 50 through 64 years (aHR 0.40 [95% CI: 0.34, 0.48]), and �65 years (aHR 0.53 [95% CI: 0.48, 0.58]) between 1 April 2022 and 31 August 2022 43 .
NMV/r was associated with reduced odds of hospitalization among patients who were unvaccinated (aOR 0.46 [95% CI: 0.27, 0.77]), vaccinated with one to two doses (aOR 0.40 [95% CI: 0.20, 0.79]), and vaccinated with three or more doses (aOR 0.47 [95% CI: 0.29, 0.74]) compared to no treatment during periods of Omicron BA.4/BA.5 predominance 48 .A second study reported similar reduction in hospitalizations among those who had received primary series or booster mRNA vaccines (50% risk reduction for both) compared to the overall population of patients treated with NMV/r (51% risk reduction) 43 .Likewise, sotrovimab reduced hospitalizations by 57% in vaccinated patients vs. 55% in all treated patients compared to no monoclonal antibody 45 , and oral antiviral treatments (NMV/r and molnupiravir) were associated with significantly lower death rates vs. no oral antivirals regardless of vaccination status 46 .However, two studies also reported greater oral antiviral treatment effect in unvaccinated or partially vaccinated patients compared to fully vaccinated patients 42,46 .

Discussion
After screening more than 2,500 articles published as of March 10, 2023, 58 studies reporting on the impact of COVID-19 vaccination and outpatient treatment on the economic burden (in terms of HCRU and costs) of the disease in the US were included in this SLR.All included studies reported HCRU outcomes stratified by treatment and/or vaccination status and one reported cost data stratified by vaccination status.Overall, the introduction of COVID-19 vaccines and outpatient treatments have had a significant positive impact on HCRU in the US.Most of the included studies reported a reduction in the risk of COVID-related hospitalizations among treated patients and/or patients who received an original monovalent primary series vaccine plus booster dose compared with no treatment or vaccination.Receipt of a booster vaccine was associated with as much as an 81% reduction in the risk of COVID-related hospitalization compared to primary series vaccination, while receipt of an outpatient treatment was associated with as much as 72% reduction in risk compared to no treatment.Other evidence also supported reduced rates of ICU admission among hospitalized patients, as well as reductions in other HCRU outcomes (e.g.length of stay, ED and urgent care clinic encounters), in treated and/or vaccinated patients.
Specifically, receipt of a booster vaccine was associated with a reduced risk of hospitalization among adults and a reduced risk of ED and urgent care clinic visits among adolescents compared with no vaccination across studies.Administration of a booster vaccine was also associated with reduced rates of hospitalization and ICU admission compared with administration of only the primary vaccine series in adults.Several studies including both periods of Delta and Omicron predominance reported that booster VE against hospitalization was lower during Omicron than Delta 23,52 , and one study found that there was a lower risk of hospitalization overall (regardless of vaccination status) following Omicron infection vs. Delta 53 .Hospitalization rates and VE against hospitalization did not differ significantly by age group 28,29,54 , although data stratified by age groups for outcomes of interest were very limited.
Outpatient treatment with NMV/r, remdesivir, sotrovimab, and molnupiravir generally reduced the risk of HCRU outcomes, such as hospitalizations and ED visits, compared to no treatment [42][43][44][45][46] .Most studies of outpatient treatments evaluated HCRU outcomes in a population of patients at high risk for progressing to severe COVID-19, including hospitalization or death (in line with Food and Drug Administration [FDA] approval/authorization language for the treatment of mild-to-moderate COVID-19) [43][44][45]47,49,51,55 . Studies witout inclusion criteria restricting analyses to highrisk patients potentially included a mix of patients at highrisk and standard-risk for progressing to severe COVID-19; therefore, these studies are not representative of patients at standard-risk of severe COVID-19 and should not be used to draw conclusions for risk of HCRU outcomes among this population 21,42,46,48,56 .The impact of age on treatment patterns and outcomes was assessed in several studies however.Treatments tended to be effective regardless of age 43,48 .Treated patients were more likely to be older than untreated patients 45,51 , and one study found age to be an independent risk factor for severe COVID-19 outcomes 21 .Few studies specifically evaluated the impact of SARS-CoV-2 variants on HCRU outcomes with COVID-19 outpatient treatment; one study found no difference in the impact of NMV/r vs. no treatment on the risk of hospitalization during Omicron BA.4/BA.5 predominance compared with prior to the emergence of these subvariants 48 .
Findings were inconclusive in terms of the impact of vaccination status on HCRU outcomes with outpatient treatment, with some studies demonstrating increased protection against hospital admission among treated, vaccinated patients (compared with unvaccinated treated patients) 42,45,46 and others demonstrating similar treatment effects regardless of vaccination status 43,48 .
The COVID-19 treatment landscape continues to evolve as the virus mutates.Although four monoclonal antibodies (bebtelovimab, bamlanivimab þ etesevimab, casirivimab þ imdevimab, and sotrovimab) have previously received emergency use authorization from the FDA for the treatment of outpatients with mild to moderate COVID-19, these treatments are no longer authorized in the US or recommended by the NIH as of April 2022 57 because the predominant Omicron subvariants are not expected to be susceptible to these treatments 58 .For example, a study of bebtelovimab identified by this SLR found no benefit with treatment in terms of 30-day all-cause hospitalization and/or mortality among patients infected with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) 49 .Studies of sotrovimab identified by this SLR did report a treatment benefit 44,45 ; however, these findings were largely based on patients treated prior to the emergence of the BA.2 subvariant and the subsequent revision of the emergency use authorization by the FDA in April 2022 59 .
There is a lack of data available on the cost impact of COVID-19 vaccination and outpatient treatment on economic burden in the US, representing a substantial gap in evidence.
The one cost study identified by this SLR reported the adjusted cost of hospitalization per day to be on average $15,400 more for unvaccinated patients compared to vaccinated patients, which would equate to an additional $37,730 per patient when considering the additional mean length of stay estimated for unvaccinated patients of 2.45 days 39 .In addition to increased length of stay, higher rates of ICU admission and IMV were significant drivers of increased costs for unvaccinated vs. vaccinated patients 39 .These findings are consistent with findings of a retrospective claims study of �1.2 million Medicare fee for service beneficiaries that was conducted between April and December 2020 (prior to the availability of COVID-19 vaccines in the US), which found the mean cost of hospitalization per patient to be $27,689 higher for patients requiring IMV compared to those hospitalized without IMV 6 .In this study patients over 75 years had a higher rate of hospitalization, but were associated with a lower hospitalization cost compared to younger patients 6 .
Our SLR found significant gaps in data on costs or HCRU stratified by age groups and/or level of risk for severe COVID-19 outcomes and therefore, no clear trends regarding the impact of these factors on vaccine and/or treatment effectiveness could be deduced.The CDC has defined age as the strongest risk factor for severe COVID-19 outcomes, along with the presence of specific underlying medical conditions, and vaccination status 50 .It is therefore of key interest to understand how economic outcomes are impacted by these factors, not only independently, but also in light of newer adapted COVID-19 vaccines in the US.
In addition to data gaps, this review encountered some other specific limitations.Data for the same patients may be represented in multiple studies given that most of the identified studies were conducted during periods of Omicron variant emergence and/or predominance and that many of the studies utilized the same regional or national data sources (such as Kaiser Permanente Southern California [KPSC], HealthVerity, the VISION network and Veterans Affairs [VA] databases).Additionally, synthesis of the evidence identified by the SLR was limited by differences in outcome definitions across studies, as well as whether adjustment for covariates was undertaken.Varying duration of follow-up also impacts the findings and the ability to compare across studies.
COVID-19 is expected to become endemic with potential peaks during fall and winter seasons 19 .It is difficult to predict when COVID-19 can be considered endemic given uncertainty around the strength and duration of immune protection from vaccination, the transmissibility of the virus, and the development of mutations resulting in new variants.With the ending of the COVID-19 Public Health Emergency (PHE) declaration in the US on 11 May 2023, vaccines and treatments will remain available, and the US Department of Health and Human Services have noted that access to vaccines and certain treatments (including NMV/r and molnupiravir) will generally not be affected 18 ; however, the national reporting of COVID-19 data by the CDC has changed towards an approach more typical of endemic disease monitoring, focusing on measures of severe illness and healthcare system capacity rather than virus transmission 60 .
Thus, evaluation of HCRU and cost outcomes remain of high priority as COVID-19 shifts to a new phase, and published literature on these topics continue to evolve.Since the searches for this SLR were updated in March 2023, additional studies demonstrating the positive impact of booster vaccines and outpatient treatments on HCRU outcomes, including hospitalizations, ICU admissions, and ventilation use, during periods of Omicron predominance have been published [61][62][63][64] .In particular, while this SLR only identified studies of original monovalent vaccines, relevant studies on the HCRU impact of bivalent vaccines are now emerging [65][66][67][68] ; these studies suggest that mRNA based bivalent booster doses provide additional protection against hospitalization, ICU visits and ED/urgent care clinic encounters, though with waning effectiveness over time [65][66][67][68] .In terms of recently published outpatient treatment studies, two emulations of randomized target trials based on VA databases reported that treatment with NMV/r or molnupiravir reduced the risk of hospital admission/death at 30 days vs. no treatment regardless of the predominant variant being Omicron BA.1/ BA.2 or BA.5 and regardless of vaccination status 63,64 .Additionally, while the studies identified by the SLR generally evaluated outcomes associated with acute COVID-19, a study reporting on post-acute hospitalization has now been published; treatment with NMV/r was associated with a reduced risk of post-acute hospitalization vs. no treatment at 180 days among patients who had at least one risk factor for progression to severe illness 69 .
To our knowledge, this is the first SLR conducted with a focus on how COVID-19 vaccines and outpatient treatments have impacted HCRU and costs in the US.More general global SLRs of the economic impact of COVID-19 itself have been conducted, generally without specifically assessing the influence of treatment or vaccination 70,71 .One global SLR of remdesivir studies found that COVID-19 treatment with remdesivir (largely among hospitalized patients) was associated with decreases in hospital and ICU bed occupancy 72 .

Conclusions
This comprehensive SLR identified and synthesized the available evidence demonstrating the impact of COVID-19 interventions (specifically vaccines and outpatient treatments) on the economic burden of COVID-19 in the US.The identified studies were heterogenous in terms of study design, outcome measures, and patient populations.Overall, these studies demonstrated a significant positive impact of COVID-19 vaccination and targeted outpatient treatment administration on HCRU in the US, including during periods of Omicron predominance.However, significant gaps were identified in terms of the following: cost data; HCRU associated with long COVID; and data for patients infected with the most recently circulating Omicron variants (such as XBB and its sublineages).These are important areas of continued research to inform clinical and policy decision-making in the US as we move beyond the pandemic into a new phase of COVID-19.

Declaration of funding
Funding for this study was provided by Pfizer, Inc. Employees of Pfizer were involved with the study design, interpretation of data, writing of the manuscript, and decision to submit the paper for publication.

Declaration of financial/other interests
FD, MDF, JY, SL, MMM, JN, ACS, MG, and AY are employees of Pfizer Inc. and may hold stock or stock options.VP, SNG, JK, PA, NS, and HB are employed by Evidera, a part of Thermo Fisher Scientific that provides consulting and other research services to pharmaceutical, medical device, and related organizations.In their salaried positions, VP, SNG, JK, PA, NS, and HB work with a variety of companies and are precluded from receiving payment or honoraria directly from these organizations for services rendered.Evidera received payment from Pfizer Inc. for the conduct of this study.

Figure 1 .
Figure 1.PRISMA Diagram of study attrition.�Grey literature sources were identified via hand-searching of the bibliography lists of relevant SLRs/meta-analyses.Abbreviations.HCRU, healthcare resource utilization; SLR, systematic literature review.

Figure 2 .
Figure 2. Timeline of data collection period of included studies.Light grey shading represents time periods of Delta predominance in the US, dark grey shading represents Omicron predominance.Prior to Delta emergence, Alpha was the predominant strain in the US.The y-axis presents the first author, publication year, and summary of the main interventions assessed for each study.Black bars correspond to studies assessing the impact of vaccines and white bars represent studies assessing the impact of treatments.Abbreviations.mRNA, messenger ribonucleic acid; NMV/r, nirmatrelvir/ritonavir; Vx, vaccine.

Figure 3 .
Figure 3. Effectiveness against hospitalization for booster vs. primary series vaccination (panel a), booster vs. no vaccination (panel B), and treatment vs. no treatment (panel C).

Table 1 .
Study Selection criteria.SLRs and meta-analyses † � Vaccines classified as between vaccine approval (i.e.biological license application [BLA] or emergency use authorization [EUA] were considered for inclusion. � Testing among symptomatic and asymptomatic patients � Consultations via telehealth/telemedicine Costs � Total costs (direct and indirect) � Direct costs related to HCRU outcomes of interest (see above) � Indirect costs: loss of productivity, absenteeism, presenteeism, and loss of school days � Total economic loss related to COVID-19 � Outcomes not related to economic burden (e.g. economic models or analyses) Study design Comparative observational studies, including prospective and retrospective cohort studies, case-control studies, and cross-sectional analyses � Clinical trials � Pharmacodynamic/pharmacokinetic studies � Genetic studies � Cellular/molecular studies � Case reports or case series � Narrative reviews � Qualitative studies (e.g.interviews, focus groups) � † Relevant SLRs were excluded but flagged for cross-checking of bibliographies against the list of included publications.Abbreviations.CI, confidence interval; COVID-19, Coronavirus disease 2019; ED, emergency department; FDA, United States Food and Drug Administration; GP, general practitioner; HCRU, healthcare resource utilization; HR, hazard ratio; ICU, intensive care unit; OR, odds ratio; RR, rate ratio; SD, standard deviation; SE, standard error; SLR, systematic literature review; VE, vaccine effectiveness.vaccination (n ¼ 35; 60.3%), booster vaccination vs. primary series vaccination (n ¼ 11; 19.0%) of original monovalent vaccines, and treatment vs. no treatment (n ¼ 11; 19.0%).