Egalement disponible en francais sous le titre : Directives mises a jour sur les doses de rappel du vaccin contre la COVID-19 au Canada To obtain additional information, please contact:# 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 of interest.

# BACKGROUND
On September 1, 2022, NACI published Recommendations on the use of bivalent Omicroncontaining mRNA COVID-19 vaccines. This followed Health Canada's authorization of the Moderna Spikevax BA.1 Bivalent (50 mcg) Omicron-containing vaccine as a booster dose for adults 18 years of age. The statement outlined recommendations for the use of this bivalent Omicron-containing mRNA vaccine as a booster dose in specific populations, ahead of the uncertain trajectory of the COVID-19 pandemic in the coming months, and how this new vaccine fit into the current landscape of the Canadian COVID-19 vaccination program. Since that time:
- On October 7, 2022, Health Canada authorized the use of the Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) COVID-19 vaccine as a booster dose in individuals 12 years of age. The Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) COVID-19 vaccine is the second bivalent Omicron-containing mRNA COVID-19 vaccine authorized for use in Canada.  The epidemiology of COVID-19 continues to change and there is still considerable uncertainty regarding the likelihood, timing, and severity of potential future COVID -19 waves. It is possible that, consistent with other respiratory viruses, the incidence of COVID-19 may increase in late fall and winter and/or that new variants of concern (VOCs) may emerge.  Although Omicron and its sublineages have largely been associated with less severe illness compared to previous VOCs, the severity of Omicron sublineages BA.4 and BA.5 in comparison to other Omicron sublineages is currently unclear, and data are still emerging at this time (1)(2)(3) .  The Omicron variant has demonstrated partial evasion of immunity conferred by the 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 sub lineages BA.4 and BA.5 may be greater than that exhibited by previous Omicron sub lineages, although evidence is still emerging at this time.  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.
NACI continues to strongly recommend a primary series with an original mRNA vaccine in all individuals 5 years of age and up, and that children 6 months to 4 years of age may receive a primary series with an original mRNA vaccine. NACI has also previously provided recommendations for a booster dose with an authorized COVID-19 vaccine for all adults, adolescents, and children 5-11 years of age. Immunization of those who are eligible for vaccination but have not yet received their recommended doses (primary series or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose will be most important for older adults (i.e., 65 years of age) and other populations at increased risk of severe COVID-19 disease (e.g., individuals with immunocompromising conditions).
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. Further information on NACI's process and procedures is available elsewhere (4,5) .

# OVERVIEW OF EVIDENCE
Evolving epidemiology  Canada experienced a resurgence in confirmed SARS-CoV-2 infections during the 2022 summer months, driven primarily by the Omicron BA.4 and BA.5 sublineages. Although the number of confirmed SARS-CoV-2 infections has decreased in recent weeks, test positivity remains elevated compared to historical trends and is considered high compared to other low points during the Omicron period. It is also possible that, consistent with other respiratory viruses, the incidence of COVID-19 will increase again in the late fall and winter, 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 epidemiology update.  Indicators of disease severity (i.e., hospitalizations and intensive care un it  admissions) also increased during the summer wave. Recent weeks have seen a decrease in hospitalization and ICU rates; however, it is possible that disease severity indicators increase again in the late fall and winter. The incidence of severe out comes remains significantly higher in unvaccinated compared to vaccinated populations and in adults 65 years of age compared to younger age groups; current hospitalization rates in adults 80 years of age are higher than pandemic averages.  Even though Omicron and its sublineages 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 

# 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 either infection or vaccination alone. However, the duration of protection from hybrid immunity has yet to be fully characterized, and evidence is still emerging regarding hybrid immunity and protection against Omicron sublineages BA.4 and BA.5, the current predominately circulating variants in Canada.  In vaccinated individuals, a previous SARS-CoV-2 infection with an 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 (2,3,(6)(7)(8) . However, preliminary evidence also suggests that in vaccinated individuals, protection a gainst reinfection is lower against Omicron BA.5, compared to earlier Omicron sublineages (i.e., BA.2), highlighting the potential immune-escape capability of Omicron BA.5 (3,6,9) .
- 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 coverage (both with a primary series and with additional doses) compared to younger adults (10) , and according to recent seroprevalence data, are less likely to have been infected during the Omicron wave compared to younger adults and adolescents (11) .  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 (12,13) . Individuals should carefully assess their individual risk (i.e., risk of SARS-CoV-2 infection and severe outcomes from COVID-19) if choosing to delay the interval between SARS-CoV-2 infection and vaccination beyond those suggested.

# Vaccine effectiveness of original COVID-19 booster vaccines
- Evidence has shown a reduced vaccine effectiveness (VE) of original COVID-19 vaccines against Omicron compared to VE observed against 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, and decreases considerably over time in most studies (14)(15)(16)(17)(18)(19)(20)(21) . However, current data suggests 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 while it remains above 75% up to 26 weeks from the first booster in most studies (22)(23)(24)(25)(26) , the duration of protection is not yet fully characterized. The majority of available studies were conducted while Omicron BA.1 and BA.2 were the predominately circulating sublineages, and data on VE waning against Omicron BA.4 and/or BA.5 are limited at this time (27,28) .  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 (22) . VE studies from Canada and Israel have also demonstrated additional protection compared to a first booster, including against severe disease (29)(30)(31)(32)(33) . However, the duration of protection from a second booster dose is currently unknown.  (34) showed that Moderna Spikevax BA.1 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 BA.1 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, pericarditis or deaths reported during the study period. No new safety signals were identified with Moderna Spikevax BA.1 Bivalent (50 mcg). However, given the number of participants enrolled in the bivalent clinical trial, it is unlikely that rare adverse events would be detected. NACI will monitor post-market safety surveillance data as it emerges and update its recommendations as needed.  The levels of antibodies produced by Moderna Spikevax BA.1 Bivalent (50 mcg) as a booster dose against the original strain were superior to those obtained in Phase 3 studies of Moderna Spikevax original, for which clinical efficacy was demonstrated (35) . However, the clinical relevance (i.e., applicability to VE) of the changes in neutralizing antibody levels observed with Moderna Spikevax BA. 

# Potential benefits of bivalent Omicron-containing vaccines
- Omicron and its sublineages are antigenically distinct from the original SARS-CoV-2 virus, as well as earlier SARS-CoV-2 VOCs, with BA.1 and BA.4/BA.5 emerging as some of the most antigenically distinct sublineages observed to date (37) . Given the potential for substantial virus evolution and uncertainty about the emergence of future variants, modification of the strain composition of COVID-19 vaccines is expected to broaden immune protection against divergent SARS-CoV-2 spike protein antigens. Available data, including clinical data on immune responses against BA.1 and BA.4/BA.5 with bivalent Omicron-containing mRNA vaccines, suggest that inclusion of an Omicron component in an updated booster vaccine composition may have benefits in the fo rm of increased protection against Omicron sublineages (38) , although no effectiveness data is currently available. Booster doses with bivalent Omicron-containing mRNA vaccines are expected to 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 (37) .  Infection with Omicron elicits a robust and broadly cross-reactive antibody response (39) .
This includes an elevated antibody response against Omicron BA.1 and BA.4/BA.5 (40) . Real-world evidence to date demonstrates that in 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 (2,3,(6)(7)(8) .  In a clinical trial, individuals who received a second booster dose with Moderna Spikevax BA.1 Bivalent (50 mcg), and who had no evidence of prior SARS-CoV-2 infection, had larger relative increases in neutralizing antibody titres against Omicron BA.1 and BA.4/BA.5 from pre-to post-second booster when compared to those who had evidence of prior SARS-CoV-2 infection. Individuals who received a second booster dose with Moderna Spikevax BA.1 Bivalent (50 mcg) who had evidence of prior SARS-CoV-2 infection, had significantly higher levels of neutralizing antibody titres against Omicron BA.1 and BA.4/BA.5 at both time points (pre-and post-second booster) compared to individuals without evidence of prior infection, however with a smaller relative increase from pre-second booster levels. Similar data were not available for Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) or BA.1 Bivalent (30 mcg).  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 greater and more rapidly-induced immune response from a bivalent Omicron-containing mRNA COVID-19 vaccine.
Post-market safety of original 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 appears to be lower than the risk following the second dose of the primary series (41)(42)(43)(44)(45)(46)(47)(48) . 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 original (50 mcg) booster doses have been administered to individuals under the age of 30, with even more limited use in adolescents 12-17 years of age given that preferential vaccine recommendations for the Pfizer-BioNTech Comirnaty product for those under the age of 30 exist in many countries and the very limited authorization of adolescent booster doses using Moderna Spikevax original (50 mcg) to date.
- Preliminary post-marketing surveillance data from the US (41) and France (43) did not identify a statistically significant difference in the rates of myocarditis following administration of the Moderna Spikevax (50 mcg) original booster doses compared to Pfizer-BioNTech Comirnaty (30 mcg) booster doses. Of note, during the period of surveillance, in the US, Moderna Spikevax original (50 mcg) was authorized as a booster dose for use among individuals aged 18 years and, in France, Moderna Spikevax original (50 mcg) was recommended for use as a booster dose among individuals aged 30 years.  NACI will also continue to monitor post-market safety and surveillance data and update its recommendations as needed.
Ethics, equity, feasibility, and acceptability 

# Other considerations
- As an immunological correlate of protection has not been determined for COVID-19 at this time, it is unknown how the increased neutralizing antibody responses observed with bivalent Omicron-containing mRNA COVID-19 vaccines are related to protection against severe outcomes from COVID-19.  There are no clinical data currently available for the use of Pfizer -BioNTech Comirnaty BA.4/5 Bivalent (30 mcg). All data available to date are either preclinical, or indirect clinical data using a similar vaccine candidate (i.e., Comirnaty BA.1 Bivalent or Comirnaty BA.1 Monovalent). NACI will continue to monitor and assess clinical data for Comirnaty BA.4/5 Bivalent as it becomes available.  The limited evidence available to date indicates that bivalent Omicron-containing mRNA COVID-19 vaccines induce stronger and more robust immune responses to the Omicron VOC and sublineages, compared to original mRNA vaccines. Currently, there are no clinical data comparing the immune response induced by BA.1 bivalent vaccines to that induced by BA.4/BA.5 bivalent vaccines.  Real-world evidence from adult populations (18 years of age) suggest that after a twodose primary series, Moderna Spikevax original (100 mcg) may result in higher VE compared to Pfizer-BioNTech Comirnaty original (30 mcg) (49) and is also associated with a higher seroconversion rate among adult immunocompromised patients (50) . Booster vaccination with Moderna Spikevax original (50 mcg) was also found to be more effective than Pfizer-BioNTech Comirnaty original (30 mcg) within the first 12 weeks following vaccination, during a period of Delta followed by Omicron variant dominance (51) . However, the relative effectiveness of a booster dose of Moderna Spikevax BA.1 Bivalent (50mcg) compared to Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) is yet to be determined.  Although the number of confirmed SARS-CoV-2 infections has decreased in recent weeks, the future trajectory of the COVID-19 pandemic remains unclear and there remains considerable uncertainty regarding the evolutionary trajectory of SARS-CoV-2. Therefore, it remains a possibility that future waves of COVID-19 are driven by novel and distinct VOCs. At this time, is it unknown if an Omicron BA.1 or an Omicron BA.4/BA.5 bivalent vaccine will be more protective against future waves of COVID-19 or future SARS-CoV-2 VOCs. However, since all authorized bivalent vaccines to date contain an Omicronspecific component, any authorized bivalent mRNA COVID-19 vaccine is likely to provide a broad immune response against Omicron sublineages, other VOCs, as well as potential future variants. As the evidence base evolves and the epidemiology of circulating variants changes, if there is an advantage of one bivalent Omicron -containing vaccine over the other, NACI will revisit its recommendations accordingly, including issuing advice on a recommended interval between vaccine doses.  No participants in the Moderna Spikevax BA.1 Bivalent or Pfizer -BioNTech Comirnaty BA.1 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 (e.g., influenza vaccination), are currently limited. However, no specific safety concerns have been identified to date (52)(53)(54)(55)(56)(57)(58) . Studies to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing.
- Currently, there are no clinical data available on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as a primary series, as a first booster dose or as part of a heterologous vaccine series. All participants in the Moderna Spikevax BA.1 Bivalent and Pfizer-BioNTech Comirnaty BA.1 Bivalent clinical trials were administered the vaccine as a second booster dose after a homologous primary series and first booster dose (38) . 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 booster dose, regardless of number or type of doses previously received. NACI will continue to monitor new evidence as it becomes available.  Although not authorized or recommended for use as part of a primary series, if a bivalent Omicron-containing mRNA COVID-19 vaccine is administered in error as part of a primary series, this dose should be considered valid as part of the primary series. With regard to the product offered;  Individuals who have received an mRNA COVID-19 vaccine as part of a fall COVID-19 vaccine booster program do not require an additional dose of a COVID-19 vaccine at this time. This includes individuals who were vaccinated using any authorized original or bivalent mRNA COVID-19 vaccine. Both original and bivalent mRNA COVID-19 vaccines will boost immune responses and are likely to provide significant protection against hospitalization and severe disease. This recommendation will be reassessed throughout the winter season, as new evidence becomes available.  NACI continues to recommend that COVID-19 booster doses given as part of the fall program may be offered at an interval of 6 months after a previous COVID-19 vaccine dose or SARS-CoV-2 infection. However, a shorter interval of at least 3 months may be considered particularly in the context of heightened epidemiologic risk, evolving SARS-COV-2 epidemiology, as well as operational considerations for the efficient deployment of the fall vaccine program. Based on what is known at this time about the virus and vaccines, it is not expected that a booster dose will be routinely provided every 3 months.  NACI continues to recommend that for all individuals aged 5 years and older, concurrent administration of other vaccines (e.g., seasonal inactivated influenza vaccine) and any dose of a COVID-19 vaccine, regardless of product offered, is acceptable and may increase program efficiency.  (50 mcg) was also found to be more effective than Pfizer-BioNTech Comirnaty original (30 mcg) during a period of Delta followed by Omicron variant dominance. However, these studies were conducted prior to the emergence of the Omicron BA.4/BA.5 VOC, and their applicability to all Omicron sublineages is uncertain.  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 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 will continue to monitor evidence as it emerges, and update recommendations as needed.  At this time, there is a high degree of uncertainty with regards to future booster dose recommendations. To date, SARS-CoV-2 does not have a seasonally established pattern of spread, and the beneficial effects of cumulative population immunity are not yet fully realized. As such, these recommendations apply specifically to NACI's guidance for fall 2022 booster dose programs.  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.

# RECOMMENDATIONS

# NACI RESEARCH PRIORITIES
- Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of both the original, and bivalent mRNA COVID-19 vaccines, through clinical trials and studies in real-world settings, including relative VE between COVID-19 vaccine products, degree and duration of protection conferred by each booster dose against circulating variants. Research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as Multisystem Inflammatory Syndrome in Children (MIS-C), post-COVID-19 condition (long COVID), or infection-induced myocarditis and/or pericarditis in older and younger adult, adolescent, and pediatric populations. 2. Continuous monitoring of vaccine coverage and acceptance in the Canadian population, specifically following the authorization of new bivalent Omicron-containing mRNA COVID-19 vaccines. 3. Further evaluations of the optimal interval between booster dose and primary series, and between any subsequent booster doses as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and booster dose administration. 4. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, to accurately inform potential risks associated with booster doses, for all COVID-19 vaccines, including bivalent Omicron-containing mRNA vaccines. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of multiple booster doses of COVID -19 vaccines. 5. Evaluations of whether bivalent Omicron-containing mRNA COVID-19 vaccines can be used as part of a primary series. 6. Continuous monitoring of COVID-19 epidemiology and VE in special populations (e.g., those with high-risk medical conditions, or social risk factors placing them at high-risk for severe outcomes) and the long-term consequences of COVID-19 in these populations.