The Novavax Heterologous Coronavirus Disease 2019 Booster Demonstrates Lower Reactogenicity Than Messenger RNA: A Targeted Review

Abstract Coronavirus disease 2019 (COVID-19) continues to be a global health concern, and booster doses are necessary for maintaining vaccine-mediated protection, limiting the spread of severe acute respiratory syndrome coronavirus 2. Despite multiple COVID-19 vaccine options, global booster uptake remains low. Reactogenicity, the occurrence of adverse local/systemic side effects, plays a crucial role in vaccine uptake and acceptance, particularly for booster doses. We conducted a targeted review of the reactogenicity of authorized/approved messenger RNA (mRNA) and protein-based vaccines demonstrated by clinical trials and real-world evidence. It was found that mRNA-based boosters show a higher incidence and an increased severity of reactogenicity compared with the Novavax protein-based COVID-19 vaccine (NVX-CoV2373). In a recent study from the National Institute of Allergy and Infectious Diseases, the incidence of pain/tenderness, swelling, erythema, fatigue/malaise, headache, muscle pain, or fever was higher in individuals boosted with BNT162b2 (0.4% to 41.6% absolute increase) or mRNA-1273 (5.5% to 55.0% absolute increase) compared with NVX-CoV2373. Evidence suggests that NVX-CoV2373, when utilized as a heterologous booster, demonstrates less reactogenicity compared with mRNA vaccines, which, if communicated to hesitant individuals, may strengthen booster uptake rates worldwide. Clinical Trials Registration NCT04889209.

As of mid-2023, a high percentage of the global population has received primary series vaccinations for coronavirus disease 2019 (COVID- 19), though significantly fewer people have received at least one booster dose.Vaccine reactogenicity, defined as local and systemic reactions, has been identified as one of the leading drivers of vaccine and booster hesitancy [1][2][3][4].Survey data from a nationally representative sample of US adults presented at the September 2023 Advisory Committee on Immunization Practices meeting indicated that adults 18-49 years of age were less likely than adults 50-64 years of age to get an updated COVID-19 vaccine, though both groups were less likely to be vaccinated than adults aged ≥65 years [5].The higher prevalence of hesitancy among younger adults enhances the relevance of this information, which could impact uptake in the population.Prior experience with vaccine-associated side effects may have contributed to the observed differences, as reactogenicity is often higher in adults <65 years of age compared to adults ≥65 years of age.In other studies, the side effects associated with messenger RNA (mRNA) vaccinations have been shown to disrupt work activities, lead to workplace absenteeism among healthcare workers [2,6,7], and reduce future willingness to receive booster vaccinations [2,3].Surveys have found that the acceptance rate of various hypothetical vaccines was dependent on the incidence and severity of side effects, and that participants would prefer vaccines with less reactogenicity [1,8], regardless of efficacy differences [8].A Health Canal survey found that adults aged ≥65 years were hesitant to receive the bivalent mRNA booster shot and reported that the top reasons for not receiving the vaccine were not knowing if the newly formulated vaccine was safe (40.73%) and concern over potential side effects (31.05%).At the time of the survey, only 42.4% of older adults, a demographic of high-risk for COVID-19, had opted to receive an updated vaccine dose [9].Vaccine hesitancy is often linked to a fear of adverse reactions, and this may be exacerbated as the COVID-19 pandemic transitions to an endemic state.As the perceived risk of COVID-19 decreases, individuals may become more sensitive to vaccine-associated adverse reactions.With the The Journal of Infectious Diseases R E V I E W increasing number of adult vaccines, including those that help protect against influenza and respiratory syncytial virus, simultaneous administration with COVID-19 vaccines may improve uptake, facilitate catch-up, and reduce the number of visits, but any increase will likely rely on the communication of acceptable adverse reaction rates [10,11].

EVALUATION OF PLATFORM-SPECIFIC COVID-19 VACCINE REACTOGENICITY
The incidence and severity of reactogenicity following primary series vaccination is well understood from the outcomes of large clinical trials [12][13][14][15][16][17][18].A recent systematic review and meta-analysis compared the local and systemic reactogenicity of primary series mRNA (including BNT162b2  [19].The study concluded that vaccine platform type influences the degree of adverse events and that mRNA vaccines were the most reactogenic when compared with viral vector, protein-based, and inactivated vaccines [19].The lack of standardization of COVID-19 vaccine trial designs such as vaccination and data collection schedules, variable data recording methods, inclusion of different symptom types, and the use of various reactogenicity and severity definitions and grading schemes makes these comparisons challenging [19]. Despite the widespread utilization of different vaccine technologies for primary series vaccinations, recommendations for future booster vaccinations will likely focus on mRNA and protein-based platforms.Viral vector-based vaccines, such as Ad26.COV2.S, are not ideal for boosting due to development of vector-specific immunity [20][21][22].By comparison, mRNA and protein-based technologies offer higher vaccine efficacy, a demonstrated safety profile, and in the case of protein vaccines, more manageable storage/handling characteristics.Dependent on regulatory guidelines, many prospective vaccine recipients can receive a booster dose with a different vaccine type than that of their primary series vaccine (a heterologous booster) [23][24][25].

METHODS
A targeted literature review was conducted to characterize the reactogenicity of mRNA and NVX-CoV2373 COVID-19 booster vaccination following any mRNA primary series regimen.Using the ProQuest Dialog platform the following databases were searched with no date restraints: BIOSIS Previews, Embase, Embase Preprints, Medline, and publicly available content.This targeted literature search included articles published up to July 2023.Title and abstract terms were searched for "NVX-CoV2373, or Nuvaxovid, or Novavax" and "mRNA, or mRNA-1273, or BNT162, or Moderna, or Pfizer."Targeted publications included clinical trials or real-world evidence studies that assessed the reactogenicity of NVX-CoV2373 and/or an mRNA vaccine used as boosters following any mRNA primary series vaccination regimen.Only studies that reported booster dose reactogenicity (local and/or systemic adverse events) were included in this review.Similarly, studies that did not include participants with mRNA primary series vaccination regimen, those that solely focused on immunocompromised populations, and studies on nonhuman subjects were excluded from this review.

RESULTS
A National Institute of Allergy and Infectious Diseases (NIAID) study titled "A Phase 1/2 Study of Delayed Heterologous SARS-CoV-2 Vaccine Dosing (Boost) After Receipt of Emergency Use Authorization (EUA) Vaccines" (NCT04889209) has generated two publications (Table 1) [26,27].Taken together, they allow for a comparison of booster dose reactogenicity following different vaccine regimens.In brief, this study is an ongoing, open-label, nonrandomized, adaptive-design clinical trial in adults ≥18 years of age within the United States.The adaptive design permits the addition of new study arms and an increase in sample size as vaccines are awarded Emergency Use Authorization by the US Food and Drug Administration (FDA) and/or as updated variant-adapted vaccines become available.The study aims to assess the safety, reactogenicity, and immunogenicity of a delayed (≥12 weeks) homologous and heterologous vaccine boost following primary series administration of authorized/approved COVID-19 vaccines.Primary series vaccine regimens include two vaccinations of mRNA-1273 (Moderna, 100 µg dose), two vaccinations of BNT162b2 (Pfizer, 30 µg), or one or two vaccination(s) of Ad26.COV2.S (Janssen, 5 × 10 10 viral particles).The mRNA-1273 vaccine booster dose studied was higher (100 µg) than the currently approved dose, which is 50 µg.The study has currently produced two publications: publication 1 includes individuals who were boosted with mRNA-1273, BNT162b2, or Ad26.COV2.S COVID-19 vaccines, thus providing nine different combinations of primary vaccination and booster [26]; publication 2 includes participants boosted with NVX-CoV2373 (5 µg recombinant spike [rS] protein + 50 µg Matrix-M adjuvant) (Table 1).Both publications had populations with relatively small sample sizes, and those boosted with NVX-CoV2373 were slightly younger than those boosted with mRNA vaccines (Table 1).Data regarding local and systemic reactogenicity were recorded using a memory aid survey and documented on a data collection form for 7 days postvaccination.For reactogenicity severity measurement, each given sign or symptom for a participant's reactogenicity event was counted once under the maximum severity for all postadministration assessments.Participants were also assessed for delayed-onset local reactions through 14 days after each vaccination.
that mRNA platforms might not display a linear dose-dependent relationship in reactogenicity when administered as a booster.Despite this, the trend of mRNA-1273 showing greater reactogenicity than BNT162b2 has been supported in other studies and surveys [19,29], though more robust real-world evidence is needed.Additionally, an early pandemic study (Comparing COVID-19 Vaccine Schedule Combinations [Com-COV2]) investigating heterologous primary series regimens similarly found that combinations including mRNA-1273 (100 µg) elicited higher reactogenicity than those including BNT162b2 (30 µg) and that combinations with either mRNA option were generally more reactogenic than those that included NVX-CoV2373 [30].

DISCUSSION
Though NVX-CoV2373 is a protein-based vaccine, the results of these studies should not be directly applied to other proteinbased options.Due to the inherently low immunogenicity of recombinant proteins, adjuvants are typically used to enhance the vaccine-mediated immune response of protein-based platforms [34,35].The currently authorized and investigational protein-based COVID-19 vaccines each utilize different adjuvants that may lead to unique reactogenicity profiles.NVX-CoV2373 includes a saponin-based adjuvant known as Matrix-M, while other vaccines utilize an oil-in-water emulsion such as SQBA (HIPRA), aluminum hydroxide gel and CpG1018 (Clover Biopharmaceuticals, Biological E. Limited), or squalene-based AS03 (SK Bioscience Co, GSK plc, Sanofi) [36].Uniquely, Matrix-M has been found to have a timerestricted occurrence at the injection site and to rapidly distribute to the draining lymph nodes, which is thought to support its favorable reactogenicity profile [37].The variation among the protein-based vaccines creates the need for additional studies to compare booster dose reactogenicity among different protein-based COVID-19 platforms to understand the impacts of the adjuvants, protein, and dose level.
The overview discussed here is limited by the current paucity of studies, as few rigorous comparative studies are available.In these studies, no homologous booster regimens of NVX-CoV2373 were investigated due to the timing of vaccine availability and logistics.Additionally, we chose to exclude discussion of viral vector and other vaccine platforms to develop a more focused assessment of mRNA and protein-based boosters.An additional assessment that includes investigation of viral vector vaccines used as primary series vaccinations may be warranted to understand the potential combinations of vaccines and their outcomes more completely.A comparative analysis designed to test differences among vaccine options is warranted.Future research that investigates the duration of symptoms and the incidence of rare events that have been infrequently observed, such as severe local and systemic symptoms, would be informative.This targeted review was unable to assess the observation that some vaccines have shown a correlation between increased neutralizing antibodies and increased reactogenicity [38,39], and the clinical significance (i.e., impact on vaccine effectiveness) of this observation remains unknown.Future real-world studies investigating the impacts of reactogenicity on productivity and school/workplace absenteeism would offer more detailed insights into vaccine-specific side effects and their societal consequences.

CONCLUSIONS
The results of different trials and real-world evidence have shown that the NVX-CoV2373 heterologous booster was associated with reduced incidence and severity of local and systemic e500 • JID 2024:230 (15 August) • Marchese et al adverse events compared with mRNA-1273 and BNT162b2.The reactogenicity of COVID-19 vaccines may become a focal point as the world transitions from a pandemic to an endemic state.Though the reviewed data included vaccines with compositions based on the original Wuhan spike protein, in the absence of changes to dose concentrations or vaccine components (i.e., mRNA vaccine lipid nanoparticles, or protein-based vaccine adjuvant), it is unlikely that the updated variant-based formulations will have a significant impact on the observed reactogenicity trends.These findings provide practical insights for healthcare providers and the public as they weigh the benefits and risks of additional COVID-19 vaccinations.