On June 29, 2022, NACI published interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. The statement outlined recommendations for booster doses in specific populations ahead of the uncertain trajectory of the COVID-19 pandemic in the coming months. Since that time:  On September 1 2022, Health Canada authorized the use of Moderna Spikevax Bivalent (50 mcg) COVID-19 vaccine as a booster dose in adults 18 years of age. The Moderna Spikevax Bivalent (50 mcg) COVID-19 vaccine is the first bivalent Omicron BA.1containing mRNA COVID-19 vaccine authorized for use in Canada.  The epidemiology of COVID-19 continues to change and there is still considerable uncertainty with regard to the likelihood, timing, and severity of any potential future COVID-19 waves. It is possible that, consistent with other respiratory viruses, the incidence of COVID-19 may increase in the later fall and winter seasons and that new variants of concern (VOCs) may emerge.  The emergence of Omicron subvariants BA.4 and BA.5 have led to a resurgence in COVID-19 cases nationally, and these subvariants currently make up the majority of new COVID-19 cases in Canada (previous Omicron subvariants, including Omicron BA.1 make up <5% of new COVID-19 cases in Canada). Nationally, indicators of disease severity, including hospitalizations and deaths, have also increased during the summer wave (1) .  Although Omicron and its subvariants have largely been associated with less severe illness compared to previous VOCs, the severity of Omicron subvariants BA.4 and BA.5 in comparison to other Omicron subvariants is currently unclear and data are still emerging at this time (2)(3)(4) .  The Omicron variant has demonstrated it is partially evasive of immunity conferred by original COVID-19 vaccines or by a previous infection with a SARS-CoV-2 variant that emerged prior to Omicron. The immune evasion exhibited by Omicron subvariants BA.4 and BA.5 may be greater than that exhibited by previous Omicron subvariants, although evidence is still emerging at this time.  Available evidence to date suggests three doses of an authorized, original mRNA COVID-19 vaccine continues to provide strong and sustained protection against severe outcomes from COVID-19.  While the proportion of Canadians vaccinated with a primary series is high, the proportion who have received at least one additional dose has plateaued at a much lower level, especially in younger age groups. NACI continues to recommend a primary series with an authorized mRNA vaccine in all authorized age groups. NACI has also provided recommendations for a booster dose with an authorized COVID-19 vaccine for all adults, adolescents, and children 5 to 11 years of age. Immunization of those who are eligible for vaccination but have n ot yet received their recommended doses (primary or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose with any authorized COVID-19 vaccine will be most important for older adults and other populations at increased risk of severe COVID-19 disease, regardless of the number of booster doses previously received.# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in -depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict o f interest. 4 | RECOMMENDATIONS ON THE USE OF BIVALENT OMICRON-CONTAINING MRNA COVID-19 VACCINES NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed. NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were updated on February 14, 2022:  To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic  To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19

# METHODS
NACI's recommendations on booster doses are based on the decision-making framework outlined in the published statement Interim guidance on booster COVID-19 vaccine doses in Canada. This framework has been updated with evolving evidence (e.g., including considerations of population level cumulative immunity and vaccine coverage) as outlined in the published statement Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. Recommendations are based on evidence of the need for (e.g., increased risk of severe illness from COVID-19 and/or increased risk of decreased protection, and waning protection due to increased time since last dose or infection) and benefit of (e.g., safety and effectiveness) booster doses in the Canadian context.
On August 18, 2022, NACI reviewed available evidence on the burden of illness in the Canadian population, as well as booster dose acceptability in the Canadian population. NACI also reviewed the available evidence on the use of the Moderna Spikevax Bivalen t COVID-19 vaccine in adults 18 years of age (including manufacturer's clinical data in the regulatory submission to Health Canada and published scientific literature). Additionally, NACI reviewed evidence of post-market safety on mRNA vaccines pertaining to myocarditis and/or pericarditis. For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to NACI's: Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
Further information on NACI's process and procedures is available elsewhere (5,6) . driven primarily by the Omicron BA.4 and BA.5 subvariants. Although signs of stabilization are being observed, significant regional variability remains, and test positivity remains elevated compared to historical trends. It is also possible that, consistent with other respiratory viruses, the incidence of COVID-19 will increase again in the later fall and winter seasons, thus posing a risk for individuals/communities and increasing pressure on health systems. For the most up-to-date epidemiology of COVID-19 in Canada, please refer to the Government of Canada's COVID-19 daily epidemiology update.  Indicators of disease severity (i.e., hospitalizations and intensive care unit  admissions) increased during the summer wave; however, signs of stabilization are being observed. The incidence of severe outcomes remains significantly higher in adults 80 years of age compared to younger age groups, and hospitalization rates in this age group are higher than pandemic averages.  Even though Omicron and its subvariants have largely been associated with a smaller proportion of severe disease compared to the previous variants, there is still uncertainty regarding the disease severity of Omicron BA.4/BA.5 relative to previous Omicron subvariants. In addition, the surge in SARS-CoV-2 infections caused in part by the increased transmissibility of Omicron BA.4/BA.5, has had a substantial impact on health system infrastructure.  NACI continues to monitor emerging data on additional Omicron subvariants of interest, such as BA.2.75. To date, there have been only a very small number of Omicron BA.2.75 sequences detected in Canada.

# Hybrid immunity & seroprevalence
- Available evidence to date shows that hybrid immunity (i.e., protection conferred from both vaccination and infection) is more robust than immunity due to infection or vaccination alone. However, the duration of protection from hybrid immunity has yet to be fully characterized, and evidence is still emerging with regard to hybrid immunity and protection against Omicron subvariants BA.4 and BA.5, the current predominately circulating variants in Canada.  In fully-vaccinated individuals, a previous SARS-CoV-2 infection with the Omicron VOC confers significant protection from reinfection with Omicron BA.4 and/or BA.5, although the durability of this protection has yet to be established (3,4,(7)(8)(9)(10) . However, preliminary evidence also suggests that in fully-vaccinated individuals, protection against reinfection is lower against Omicron BA.5, compared to earlier Omicron subvariants (i.e., BA.2), highlighting the potential immune-escape capability of Omicron BA.5.  Emerging Canadian evidence suggests that a large proportion of older adults are protected by vaccination, but may not have acquired hybrid immunity. In Canada, older adults have higher vaccination rates (both with a primary series and with additional doses) compared to younger adults (11) , and according to recent seroprevalence data, are less likely to have been infected during the Omicron wave compared to younger adults and adolescents (12) .  It is expected that individuals who have been infected with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the interval since infection, using similar immunological principles to those informing intervals between vaccine doses. Emerging evidence indicates that a longer interval between SARS-CoV-2 infection and vaccination is associated with improved immune responses to COVID-19 vaccines (13,14) .
Vaccine effectiveness of original COVID-19 booster vaccines  Evidence has shown a reduced vaccine effectiveness (VE) of currently-available COVID-19 vaccines against Omicron compared to the effectiveness observed with previous VOCs. VE against Omicron infection after a first booster dose of an original mRNA COVID-19 vaccine is approximately 60% shortly after receipt of the booster dose, an d decreases over time in most studies (15)(16)(17)(18)(19)(20)(21)(22) . However, current data suggest that original mRNA COVID-19 vaccines continue to provide significant protection against hospitalization and severe disease. Initial VE against severe disease is approximately 90% following a first booster dose, and remains above 75% up to 26 weeks from the first booster in most studies (23)(24)(25)(26)(27) ; duration of protection against severe disease is not yet known.  Evidence on VE of a second COVID-19 booster dose is currently limited. Recent data from the US have shown that during a period of Omicron BA.2 dominance, among adults at least 50 years of age, a second booster dose of an original mRNA COVID-19 vaccine provided additional protection against emergency department and/or urgent care visits due to COVID-19, as well as hospitalization, compared to those who received one booster dose of an original mRNA COVID-19 vaccine (23) . VE studies from Canada and Israel have also demonstrated additional protection compared to a first booster, inclu ding against severe disease (28)(29)(30)(31)(32) . However, the duration of this increased protection from a second booster dose is currently unknown.  (33) showed that Moderna Spikevax Bivalent (50 mcg) administered as a second booster dose to individuals 18 years of age had a similar reactogenicity profile to that of Moderna Spikevax original (50 mcg) given as a second booster dose. Also, the frequency of adverse events following Moderna Spikevax Bivalent (50 mcg) given as a second booster dose was similar or lower compared to that of a first booster dose of Moderna Spikevax original (50 mcg), and of the second dose of the Moderna Spikevax original primary series (100 mcg). There were no vaccine-related cases of myocarditis, 

# Potential benefits of bivalent vaccines
- Omicron and its subvariants are antigenically distinct from the original SARS-CoV-2 virus, as well as earlier SARS-CoV-2 VOCs, with BA.1 emerging as one of the most antigenically distinct subvariants (34) . Given the potential for substantial virus evolution and uncertainty about the emergence of future variants, modification of the strain composition of COVID-19 vaccines may broaden immune protection against divergent SARS-CoV-2 spike protein antigens. Available data, including clinical data on immune responses against BA.4 and BA.5 with a BA.1-targeted, bivalent mRNA vaccine, suggest that inclusion of Omicron in an updated booster vaccine composition may have immediate benefits in the form of increased protection against variants such as Omicron BA.4 and BA.5 (35) . The BA.1targeted, bivalent mRNA vaccines may also elicit a greater breadth of immune response, potentially providing additional protection against future variants of concern , although given the unpredictable nature of the ongoing evolution of SARS-CoV-2, this is uncertain at this time (34) .  In individuals previously exposed to SARS-CoV-2 (either through infection or vaccination), infection with Omicron elicits a robust and broadly cross-reactive antibody response (36) . This includes an elevated antibody response against Omicron BA.4 and BA.5 (37) .  In a clinical trial, individuals who received a second booster dose with Moderna Spikevax Bivalent (50 mcg), and who had no evidence of prior SARS-CoV-2 infection, had larger relative increases in neutralizing antibody titres from pre-to post-booster when compared to those who had evidence of prior SARS-CoV-2 infection. Individuals who received a second booster dose with Moderna Spikevax Bivalent (50 mcg) who had evidence of prior SARS-CoV-2 infection, had significantly higher levels of neutralizing antibody titres at both time points (pre-and post-booster) compared to individuals without evidence of prior infection, however with a smaller relative increase from pre-booster levels.  It is possible individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. Additionally, individuals who were previously infected may experience a Post-market safety of mRNA booster doses  Available surveillance data to date from Canada and international jurisdictions indicate that the risk of myocarditis and/or pericarditis following a first booster dose of an original mRNA COVID-19 vaccine using manufacturer-authorized booster dosage appears to be lower than the risk following the second dose of the primary series (38)(39)(40)(41)(42)(43)(44) . o This trend is observed for both Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original vaccine products and across all age groups (including individuals under 30 years of age, for whom the risks are highest). However, a limited number of Moderna Spikevax (50 mcg) original booster doses have been administered to individuals under the age of 30 given the vaccine recommendations/authorizations in each country for this age group. o Preliminary post-marketing surveillance data from the US (38) and France (40) have shown similar rates of myocarditis following administration of the Mod erna Spikevax (50 mcg) original or Pfizer-BioNTech Comirnaty (30 mcg) booster doses.
Of note, during the period of surveillance, in the US, Moderna Spikevax original (50 mcg) was authorized for use among individuals aged 18 years and, in France, Moderna Spikevax original (50 mcg) was recommended for use among individuals aged 30 years. o No product-specific differences between Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original have been identified with respect to the risk of myocarditis after administration of a booster dose.  In addition, preliminary safety data indicate that the risk of myocarditis and/or pericarditis associated with a second booster dose of an original mRNA COVID-19 vaccine is lower than the risk following the second dose of the primary series (44,45) .  NACI will also continue to monitor post-market safety and surveillance data and update its recommendations as needed.
Ethics, equity, feasibility, and acceptability  Given the considerable uncertainty regarding the trajectory of the COVID-19 pandemic, NACI based its recommendations on an evidence-informed framework and recommends booster doses focus on those at greatest risk of severe illness from COVID-19.  Intentions to accept a booster dose of a COVID- 19 

# Other considerations
- As an immunological correlate of protection has not been determined for COVID-19 at this time, it is unknown how the neutralizing antibody responses that have been reported from the Moderna Spikevax Bivalent clinical trial are related to the prevention of severe outcomes from COVID-19.  No participants in the Moderna Spikevax Bivalent clinical trial were concurrently administered other vaccines. Data with regard to the safety and immunogenicity of other authorized COVID-19 vaccines (including original mRNA COVID-19 vaccines) when given concurrently with other vaccines, are currently limited. However, no specific safety concerns have been identified to date (46)(47)(48)(49)(50)(51)(52) . Studies to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing.  Currently, there are no data available on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as a primary series, first booster dose or in a mixed series with vaccines other than Moderna Spikevax original. All participants in the Moderna Spikevax Bivalent clinical trial were administered Moderna Spikevax Bivalent (50 mcg) as a second booster dose after a two-dose primary series (100 mcg doses) and a first booster dose of Moderna Spikevax original (50 mcg) (35) . It is likely that the immunological benefits and safety profile will be similar in individuals receiving a bivalent Omicron-containing mRNA COVID-19 vaccine as a first booster. NACI will continue to monitor new evidence as it becomes available.  Although the authorized 50 mcg dose of Moderna Spikevax Bivalent is half of the authorized 100 mcg dose of Moderna Spikevax original administered as part of a primary series, if Moderna Spikevax Bivalent (50 mcg) is administered in error as part of a primary series, this dose should be considered valid as part of the primary series. 

# Considerations for the use of a bivalent Omicron-containing mRNA COVID-19 vaccine
- Individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant.  There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19.  There are currently no data on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as part of a primary series. NACI continues to recommend a primary series with an original mRNA vaccine in all authorized age groups. NACI   Individuals in this cohort can receive any available, authorized, mRNA COVID-19 vaccine as a booster dose, as any option is expected to provide strong protection against severe outcomes from COVID-19.  Maximizing the benefit of protection of a booster dose may be affected by the interval between doses. A longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose.
a For a first or second booster dose for adults 18 years of age and older who are not able or willing to receive an mRNA COVID -19 vaccine, a protein subunit COVID-19 vaccine (Novavax Nuvaxovid) may be offered to adults with out contraindications to the vaccine. Novavax Nuvaxovid is not currently authorized for use as a booster dose in Canada. Medicago Covifenz is not currently authorized for use as a booster dose in Canada. Janssen Jcovden COVID-19 vaccine may be offered as a first booster to individuals 18 years of age and older without contraindications to the vaccine only when all other COVID-19 vaccines are contraindicated.
NACI RESEARCH PRIORITIES 

# Immunogenicity
In this study, the primary immunogenicity analysis was based on the primary immunogenicity set which includes participants with no evidence of SARS-CoV-2 infection at baseline (pre-booster). For the pre-specified primary objectives, there were four corresponding endpoints: Individuals with prior SARS-CoV-2 infection  In addition to the primary analysis, a pre-planned subgroup analysis was also performed to assess the consistency of results in participants with evidence of prior SARS-CoV-2 infection. Based on this analysis, results in individuals with evidence of prior SARS-CoV-2 infection were consistent with results in those without evidence of prior SARS-CoV-2 infection, with regards to meeting the primary and secondary immunogenicity endpoints.  Individuals with evidence of prior SARS-CoV-2 infection had considerably higher GMTs pre-booster against both Omicron and the original SARS-CoV-2, compared to those without evidence of prior SARS-CoV-2 infection. Consequently, at Day 29 post-booster GMTs were considerably higher in those with evidence of prior SARS-CoV-2 infection, compared to those without (against both Omicron and original SARS-CoV-2). However, the GMFR from pre-booster levels was larger in those without evidence of prior SARS-CoV-2 infection compared to those with previous infection, by roughly 1.7-fold against Omicron and 1.8-fold against original SARS-CoV-2 in the Moderna Spikevax Bivalent group and 1.8-fold against Omicron and 1.9 fold in the Moderna Spikevax original group. A consistent result was observed for neutralizing antibody activity against Omicron BA.4 and BA.5 specifically.  Of note, participants with a confirmed SARS-CoV-2 infection within 3 months of enrollment were not eligible for inclusion in the trial. With an enrollment period of Feb 18 -Mar 8 2022, the majority of individuals with evidence of prior SARS-CoV-2 infection enrolled in the trial were likely not infected with the Omicron VOC.  

# APPENDIX A: MODERNA SPIKEVAX BIVALENT CLINICAL TRIAL DATA Vaccine characteristics
For complete prescribing information for Moderna Spikevax Bivalent, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the Drug Product Database. 

# Safety
The safety and reactogenicity of Moderna Spikevax Bivalent (50 mcg) administered as a second booster dose was similar to that of Moderna Spikevax original (50 mcg), given as a second booster dose (33,53) . Also, the frequency of adverse events following immunization with Moderna Spikevax Bivalent (33,35,53) was similar or lower relative to that of a first booster dose of Moderna Spikevax original (50 mcg) (54) , and of the second dose of the Moderna Spikevax original primary series (100 mcg) (55) . No new safety signals were identified. There were no vaccine related cases of death, myocarditis and/or pericarditis reported during the study period (33,53) . Given the trial was limited to 814 participants receiving the Moderna Spikevax Bivalent (n=437) and Moderna Spikevax original (n=377) vaccines (33,53) , it is unlikely that any rare adverse event would be detected. NACI will monitor post-market safety surveillance data as it emerges and update the recommendations as needed.