About vaccine efficacy and effectiveness
Vaccine efficacy indicates the level of protection a vaccine has demonstrated in clinical trials. Vaccine effectiveness refers to the protection the vaccine has provided during ‘real world’ use in the population use. Unless indicated, efficacy and effectiveness estimates relate to protection against the ancestral or pre-Omicron SARS-CoV-2 variants.
Effectiveness of bivalent COVID-19 vaccines
There are no direct data on the immunogenicity or efficacy of bivalent COVID-19 vaccines for primary course vaccination. Their preferential use for the primary course is based on superior immunogenicity and vaccine effectiveness against Omicron sub-variants, when evaluated as booster doses. Early vaccine effectiveness studies demonstrate that both BA.4/5- and BA.1- based bivalent vaccines offer excellent protection against hospitalisation and death from COVID-19current SARS-CoV-2 strains for several months.
A population-wide cohort study conducted across 4 Nordic countries during an Omicron-dominant study period reported the combined vaccine effectiveness (CVE) of Pfizer and Moderna BA.1 vaccines against hospitalisation at 74% (95% CI: 68.6 – 79.4%), and of BA.4/5 vaccines at 80.5% (95% CI: 69.5 – 91.5%).1
Similarly, the effectiveness of Pfizer or Moderna BA.4/5 vaccines against hospitalisation or death during an Omicron-dominant period was estimated at 61.8% (95% CI: 48.2– - 71.8) in a US test-negative case control study.2 In this latter study, VE estimates of Pfizer and Moderna BA.4/5 vaccines were similar (63.8% vs 60.4% respectively).2
Data from the UK Health Security Agency in people aged ≥50 years demonstrate some waning of the incremental protection from BA.1 booster doses. At 2 to 4 weeks post booster, VE against hospitalisation for Pfizer BA.1 vaccine was 47.2% (95% CI: 39.4– 51.1%) and for Moderna BA.1 vaccine was 57.8% (95% CI: 51.6– - 63.3%), dropping to 38.0% (95% CI: 31 – 44.3%) and 34.1% (95% CI: 29.2– - 38.7%) respectively at 10+ weeks.3
Bivalent vaccines also offer some protection against symptomatic infection. An observational study in Japan conducted during a BA.5- dominant period found that the effectiveness of BA.4/5 and BA.1 vaccines against symptomatic illness was similar. Combined VE of Pfizer and Moderna BA.1 vaccines was 65% (95% CI: 47 – 77) for BA.1, and combined VE of Pfizer and Moderna BA.4/5 vaccines was 76% (95% CI: 65 – 83).4
Vaccine immunogenicity and efficacy – Pfizer
Pfizer bivalent vaccines
Pfizer bivalent original/Omicron BA.4/5 formulation
An immunogenicity study (Study C4591044) investigated results in adolescents and adults aged 12 years and over who had received a primary series and first booster of Pfizer original formulation. Researchers gave participants a second booster of 30 µg of Pfizer bivalent BA.4/5 and compared the results with those of another study which had used the Pfizer original formulation for the second booster. Adults aged over 55 who received Pfizer bivalent BA.4/5 developed higher neutralising antibody titres to the BA.4/5 Omicron subvariant (geometric mean ratio 2.91, 95% CI: 2.45–3.44) than those who received Pfizer original formulation. Neutralisation of newer BQ.1.1 and XBB.1 subvariants was also higher than with the original formulation. The bivalent vaccine had non-inferior and modestly higher titres for ancestral strain neutralisation (GMR 1.38, 95% CI: 1.22–1.56). Other age groups showed similar trends (12 to 17 years; 18 to 55 years).5
Pfizer bivalent original/Omicron BA.1 formulation
Evidence for the Pfizer bivalent original/Omicron BA.1 formulation (Pfizer bivalent BA.1) is limited to immunogenicity data in participants aged over 55 years. The trial included 305 people who received Pfizer bivalent BA.1 and 305 people who received Pfizer original formulation as their second booster dose. The second booster dose was given 5 to 12 months after a primary course and first booster dose using Pfizer original formulation (30 µg). At 4 weeks after vaccination, Pfizer bivalent BA.1 resulted in 1.6 times higher neutralising antibodies against the Omicron BA.1 variant compared with the original vaccine, in people without previous infection (95% CI 1.17 to 2.08).6 Neutralising antibody titres against the ancestral virus were similar for both the Pfizer bivalent BA.1 and original formulations (geometric mean ratio 0.99; 95% CI 0.82 to 1.20).6
Immunogenicity data are not available for Pfizer bivalent BA.1 in people aged 55 years and under. However, data are available from a trial that included participants aged 18 to 55 years, in which 263 people received a Pfizer monovalent Omicron vaccine and 280 people received the Pfizer original formulation. In people who received the monovalent Omicron vaccine, neutralising antibody titres against the Omicron BA.1 variant were higher than in people who received Pfizer original formulation, to a similar degree as that seen in the Pfizer bivalent BA.1 study. These similarities in data were used to infer protection after a bivalent BA.1 vaccine in this age group.
Pfizer original formulation
A phase II/III trial of Pfizer original formulation enrolled more than 43,000 people aged ≥12 years. An interim analysis at 2 months after dose 2 reported vaccine efficacy of 95.0% (95% CI: 90.3–97.6) in preventing symptomatic laboratory-confirmed COVID-19 in people aged 16 or older years who did not have evidence of previous infection with SARS-CoV-2.7
Short-term vaccine efficacy after a single dose was 52.4% (95% CI: 29.5–68.4). A protective effect was observed starting 12 days after dose 1.
Efficacy against severe illness was estimated at 88.9% after the first dose (95% CI: 20.1–99.7). This estimate is imprecise because of the small number of people who developed severe disease and there was only a very short period of follow-up as most people then received the second dose.7
In follow-up analysis of the phase III clinical trial for Pfizer original formulation, efficacy against severe COVID-19 remained high for up to 6 months after dose 2 (95.7%, 95% CI: 73.9–99.9). Efficacy against laboratory-confirmed symptomatic COVID-19 decreased from 96.2% (95% CI: 93.3–98.1) between 7 days and <2 months after dose 2, to 83.7% (95% CI: 74.7– 89.9) between ≥4 months and 6 months.8
No data are currently available on efficacy for preventing asymptomatic infection.
Subgroup analyses showed high efficacy in:
- adults aged 65 years or older (vaccine efficacy 94.7%, 95% CI: 66.7–99.9)
- adults with at least one medical condition including obesity (vaccine efficacy 95.3%, 95% CI: 87.7–98.8).9
Pfizer conducted a randomised blinded placebo-controlled trial of approximately 10,000 participants aged 16 years and over, including 78 participants aged 16 to 17 years. The study included people who had completed a 2-dose primary schedule of Pfizer original formulation at least 6 months previously. The relative vaccine efficacy against infection across all ages was 95.3% (95% CI: 89.5–98.3) for boosted compared to non-boosted participants during a period of Delta variant circulation. Only 2 COVID cases occurred in the 16 to 17-year age cohort, both in the placebo non-booster group.10
Vaccine efficacy estimates are not available for booster doses in children aged under 16 years. A clinical trial conducted by Pfizer showed an increase in neutralising antibodies against the ancestral and early Omicron variants of SARS-CoV-2 after a first booster dose in children aged 5 to 11 years who had no evidence of past infection.11
Children aged 12 to 15 years
A study is ongoing that involves more than 2,000 adolescents aged 12 to 15 years. Early results showed that efficacy was 100% (95% CI: 78.1–100) against COVID-19 occurrence at least 7 days after dose 2 in participants with or without evidence of previous infection. There were no cases in the vaccine arm.
After dose 1 and before dose 2, there were 3 COVID-19 cases (within 11 days after dose 1) among vaccine recipients, and 12 cases among placebo recipients. Efficacy was 75% (95% CI: 7.6–95.5).
No severe cases of COVID-19 were observed in this age cohort.
The neutralising antibody response after 2 doses was higher among people aged 12 to 15 years than people aged 16 to 25 years.12 The safety profile was acceptable.12
Children aged 5 to 11 years
A study is ongoing that involves children aged 6 months to under 12 years, with results currently available for the 5–11-year age group.13 These children received the paediatric formulation of the Pfizer vaccine (10 µg dose).
Among 2,186 trial participants aged 5 to 11 years without evidence of previous SARS-CoV-2 infection, the 10 µg dose of paediatric Pfizer COVID-19 vaccine was 90.7% effective (95% CI: 67.7–98.3) at preventing laboratory-confirmed symptomatic COVID-19 from day 7 after dose 2 (with an interval of 3 weeks between doses). This was based on 3 observed cases among 1,305 paediatric Pfizer COVID-19 vaccine recipients compared with 16 cases among 663 placebo recipients. All cases were reported between July and September 2021. The 3 cases in the paediatric Pfizer COVID-19 vaccine group were mild and without fever, whereas most cases in the placebo group had documented fever. Multiple concurrent symptoms were also observed more frequently among cases in the placebo group. There were no cases of severe COVID-19 in either arm.
Neutralising antibody titres after 2 doses among 264 participants aged 5 to 11 years who received the 10 µg dose of the paediatric Pfizer COVID-19 vaccine were comparable to those observed in 253 trial participants aged 16 to 25 years who received two 30 µg doses of the formulation for people aged 12 years or older, with a ratio of 1.04 (95% CI: 0.93–1.18).5 The proportion achieving seroconversion was also similar (99.2%). Additionally, in a small subset of 34 children who received the paediatric Pfizer COVID-19 vaccine, the increase in neutralisation titre against the Delta variant from pre-vaccination to after dose 2 (29.5-fold increase) was similar to the fold-increase observed for the reference strain (36.5-fold increase).
Children aged 6 months to 4 years
Limited preliminary data are available from the ongoing phase II/III trial of the Pfizer vaccine in infants and children aged 6 months to 4 years.14 Participants received 3 doses of a paediatric formulation of the Pfizer vaccine that is one-tenth of the dose used in adults. The formulation of the vaccine used in children aged 6 months to 4 years (3 µg dose) is different to the formulation used in children aged 5 to 11 years (10 µg dose).
Among 1,456 trial participants aged 6 months to 4 years with and without evidence of previous SARS-CoV-2 infection, vaccine efficacy was estimated at 80.3% (95% CI: 13.9–96.7) against laboratory-confirmed COVID-19 from day 7 after dose 3 (with an interval of 3 weeks between dose 1 and 2, and 8 weeks between dose 2 and 3). This was based on 3 observed cases among 992 paediatric Pfizer COVID-19 vaccine recipients compared with 7 cases among 464 placebo recipients. All cases were reported between February and April 2022, a period of Omicron variant predominance.14
When considering the age sub-groups both with and without evidence of previous SARS-CoV-2 infection, efficacy against laboratory-confirmed COVID-19 from day 7 after dose 3 was:14
- 82.3% (95% CI: –8.0 to 98.3) among 886 trial participants aged 2 to 4 years
- 75.5% (95% CI: –370.1 to 99.6) among 570 trial participants aged 6 to 23 months.
Some cases of severe COVID-19 were reported after dose 2, and no cases of severe COVID-19 were reported after dose 3. Due to the small numbers of severe COVID-19 in each trial arm, efficacy could not be determined against this outcome.14
In children aged 6 months to 4 years, protective efficacy was assumed through the demonstration of an equivalent or better immune response in infants and children aged 6 months to 4 years than in young adults aged 16 to 25 years, where efficacy has previously been shown against the ancestral strain. Neutralising antibody responses after dose 3 were measured in a small subset of 82 infants and toddlers aged 6 to 23 months and 143 children aged 2 to 4 years. These were compared to the neutralising antibody responses of 170 young adults aged 16 to 25 years after dose 2. Neutralising antibodies were 1.19 times higher in those aged 6 to 23 months, and 1.30 times higher in those aged 2 to 4 years than in those aged 16 to 25 years. These neutralising antibody responses were measured against an ancestral SARS-CoV-2 strain (USA_WA1/2020), not the Omicron variant of concern. The proportion achieving seroconversion was also similar between those aged 6 months to 4 years (100%) and those aged 16 to 25 years (98.8%).14
People with specified medical conditions
The ongoing phase II/III trial includes participants with well-controlled chronic medical conditions. An interim sub-analysis in this group showed an efficacy of 95.3% (95% CI: 87.7–98.8). This was similar to the efficacy in people without these conditions (94.7%, 95% CI: 85.9–98.6).7
Data on safety, immunogenicity or efficacy of Pfizer original formulation vaccine in people living with stable HIV from the trial have not yet been published but were stated to be similar to that in other participants.
Co-administration with influenza vaccine
The UK ComFluCOV study was a phase IV randomised controlled trial of co-administration of dose 2 COVID-19 vaccine (AstraZeneca or Pfizer original formulation) with one of three seasonal inactivated influenza vaccines (adjuvanted trivalent vaccine for participants aged 65 years and older, and either cellular or recombinant quadrivalent vaccine for participants aged under 65 years). It found no significant safety concerns, and the immune response to both vaccines was preserved.15
Vaccine immunogenicity and efficacy – Moderna
Moderna bivalent vaccines
Moderna bivalent original/Omicron BA.4/5 formulation
Immunogenicity data from the Moderna clinical trial demonstrate a trend towards the BA.4/5 vaccine inducing higher neutralising activity against Omicron subvariants (including BQ.1 and XBB.1) than original vaccines or BA.1-containing vaccines.16 This study reported 5.1 to 6.3 times greater neutralising antibody levels against the BA.4/5 Omicron subvariants at 1 month after a booster dose of Moderna bivalent BA.4/5 vaccine compared with Moderna original vaccine in adults aged 18 years and over who had previously received a primary series and booster dose of Moderna original vaccine.16
Early evidence suggests a booster dose of Moderna bivalent BA.4/5 vaccine provides greater protection against hospitalisation and death from severe Omicron disease compared with a booster dose of Moderna original vaccine at 1 to 3 months in adults (63.8% vs 38.6%, respectively).2 Very few cases of hospitalisation or death from severe Omicron disease have occurred in children aged under 12 years.17
Moderna bivalent original/Omicron BA.1 formulation
A phase II/III P205 trial in more than 800 people aged 18 years or older is ongoing.18 Participants received either the Moderna bivalent original/Omicron BA.1 formulation (containing 25 μg each of both the ancestral strain of SARS-CoV-2 and the Omicron BA.1 variant) or the Moderna original formulation as a second booster dose, at least 3 months after a Moderna original primary course (using 100 μg doses) and first booster dose (50 μg) using Moderna original formulation.
At 1 month after vaccination, participants who received Moderna bivalent original/Omicron BA.1 formulation had modestly higher neutralising antibody titres against the Omicron BA.1 variant than people who received Moderna original formulation. These were 1.7 times higher (95% CI: 1.5–2.0) in people with no previous SARS-CoV-2 infection, and 1.9 times higher (95% CI: 1.5–2.4) in people with previous SARS-CoV-2 infection.
Neutralising antibody titres against the original virus were similar following a booster dose with either the original or bivalent BA.1 formulations. These were 1.3 times higher (95% CI: 1.1–1.5) in people with previous SARS-CoV-2 infection and 1.2 times higher (95% CI: 1.1–1.4) in people with no previous SARS-CoV-2 infection.18,19
Neutralising antibody titres against the BA.4 and BA.5 subvariants were 1.7 times higher (95% CI: 1.5–1.9) in people who received Moderna bivalent original/Omicron BA.1 formulation than in those who received Moderna original formulation, although absolute neutralising antibody titres were lower than those seen against the BA.1 variant.19
Binding antibody levels against previous variants such as Alpha and Delta were also similar or slightly higher in people who received the bivalent vaccine than in those who received the original vaccine.18
Moderna original formulations
Moderna original 6 months to 5 years formulation and Moderna original 6 years and over formulation are no longer available in Australia. Information on these vaccines is presented for reference and because Moderna bivalent formulations still contain the active ingredient from the original formulation.
The phase III trial of Moderna oOriginal formulation involved more than 30,000 people aged 18 years or older (mean age 51.4 years, range 18 to 95 years).20 About one-quarter were aged ≥65 years, and about one-fifth of adults in the study aged 18 to –64 years had a medical condition with increased risk of severe COVID-19.
Preliminary results of this trial at 2 months after dose 2 reported an efficacy of 94.1% (95% CI: 89.3–96.8) in preventing symptomatic laboratory-confirmed COVID-19 in participants who had not previously been infected with SARS-CoV-2. All 30 severe COVID-19 cases occurred in the placebo group, resulting in a vaccine efficacy estimate of 100% (95% CI unable to be estimated). One death due to SARS-CoV-2 infection occurred in the placebo group.
Short-term efficacy against symptomatic laboratory-confirmed COVID-19, from 14 days after the first dose and before the second dose, was 92.1% (95% CI: 68.8–99.1).
The phase I trial indicated that vaccine-induced antibodies lasted for at least 6 months after dose 2.21
In a follow-up analysis of the phase III clinical trial of Moderna original formulation,22 efficacy against severe COVID-19 remained high up to 6 months after dose 2 (97.6%, 95% CI: 92.4–99.2). Efficacy against laboratory-confirmed symptomatic COVID-19 was the same at 4 months or more to 6 months (92.4%, 95% CI: 84.3–96.8) as at 14 days to less than 2 months.22
In the phase III trial, 24.8% of participants were aged 65 years or over.23 In this subgroup, efficacy against symptomatic disease was estimated to be 86.4% (95% CI: 61.4–95.2), compared with 95.6% (95% CI: 90.6–97.9) among participants aged 18 to 64 years.
Children aged 12 to 17 years
A phase II/III trial evaluating the safety and efficacy of Moderna original formulation in 3,732 adolescents aged 12 to 17 years is ongoing.24,25
The interim results of the phase II/III trial26 showed a vaccine efficacy of 93.3% (95% CI: 47.9–99.9) in preventing symptomatic PCR-confirmed SARS-CoV-2 infection from day 14 after dose 2.27 Antibody responses (titre and seroconversion) to Moderna original formulation (measured by pseudotyped virus neutralisation assay) in this age group were similar to the response in people aged 18 to 25 years for both antibody titre and seroresponse rate.
Children aged 6 to 11 years
A phase II/III trial evaluating the efficacy of Moderna original formulation among children aged 6 months to 11 years of age is also ongoing.25,28 Limited preliminary data are available from this trial for children aged 6 to 11 years.29 Vaccine efficacy was not reliably determined due to the small number of COVID-19 cases accrued during the study (resulting in wide confidence intervals). However, the estimated vaccine efficacy against symptomatic COVID-19 was 76.8% (95% CI: –37.3 to 96.6) from 14 days after dose 2.27 The high short-term efficacy of Moderna original formulation seen in young adults suggests that the vaccine will have similar efficacy for children aged 6 to 11 years.
Good efficacy is also expected as the immunogenicity is similar between children aged 6 to 11 years and young adults aged 18 to 26 years. Neutralising antibody titres 28 days after the second dose were higher among 134 children aged 6 to 11 years who received 50 μg per dose (with a 28-day dosing interval) than among 295 young adults aged 18 to 25 years who received 100 μg per dose, with a geometric mean ratio of 1.2 (95% CI: 1.1–1.4). The seroresponse rate was also similar between these age groups, with a difference of 0.1% (95% CI: –1.9 to 2.1).30
Children aged 6 months to 5 years
Limited preliminary data are available for infants and children aged 6 months to 5 years from the ongoing phase II/III P204 trial of Moderna original formulation in infants and children aged 6 months to 11 years.25 Infants and children aged 6 months to 5 years received the paediatric formulation of Moderna original vaccine (25 µg dose).
Among 2,024 trial participants aged 6 to 23 months without evidence of previous SARS-CoV-2 infection, the paediatric Moderna original formulation was 50.6% effective (95% CI: 21.4–68.6) at preventing laboratory-confirmed symptomatic COVID-19 from day 14 after dose 2 (with an interval of 4 weeks between doses). Among 3,452 trial participants aged 2 to 5 years without evidence of previous SARS-CoV-2 infection, the paediatric Moderna original formulation was 36.8% effective (95% CI: 12.5–54.0) at preventing laboratory-confirmed symptomatic COVID-19 from day 14 after dose 2 (with an interval of 4 weeks between doses). All cases were reported between October 2021 and February 2022, and were due to the Omicron variant. There were no cases of severe COVID-19 in either arm, so efficacy could not be determined against this outcome.27
In the P204 trial, the presumed protective efficacy was assumed through immunobridging – that is, the demonstration of an equivalent or better immune response in infants and children 6 months to 5 years than the immune response in young adults 18 to 25 years, where efficacy has previously been shown against the ancestral strain. The neutralising antibody responses were measured in a small subset of 230 infants/toddlers aged 6 to 23 months and 264 children aged 2 to 5 years, and were compared to the neutralising antibody responses of 295 young adults aged 18 to 25 years. Neutralising antibodies were 1.28 times higher in those aged 6 to 23 months, and equivalent in those aged 2 to 5 years to that seen in 18-to-25-year-old adults. These neutralising antibody responses were measured against an ancestral SARS-CoV-2 strain (D614G), not the Omicron variant of concern.27
People with specified medical conditions
The ongoing phase III trial enrolled people with stable medical conditions that put them at increased risk of severe COVID-19. An analysis of this subgroup demonstrated efficacy similar to the efficacy estimated in those without risk factors for severe disease (90.9%, 95% CI: 74.7–96.7, compared with 95.1%, 95% CI: 89.6–97.7).22
Co-administration with influenza vaccine
Preliminary findings from a phase II descriptive randomised open-label study of a booster dose of Moderna original formulation administered at the same time as Fluzone high-dose quadrivalent vaccine in people aged 65 years and older showed acceptable reactogenicity and immunogenicity for both vaccines, with no safety signals.31
Co-administration has not yet been investigated in children aged 6 months to 5 years in the Moderna P204 clinical trial.
Vaccine immunogenicity and efficacy – Novavax
Two phase III trials were conducted in the United States, Mexico and the United Kingdom. Around 24,000 people received 2 doses of Novavax during the trial, and around 17,500 people received placebo.32,33
Vaccine efficacy against PCR-confirmed symptomatic mild, moderate or severe COVID-19 in serologically negative adults, with onset at least 7 days after dose 2 was:
- 90.4% (95% CI: 82.9–94.6) in the United States/Mexico trial33
- 89.7% (95% CI: 80.2–94.6) in the United Kingdom trial.32
Estimated efficacy against moderate or severe COVID-19 was:
- 100% (95% CI: 80.9–100) in the United States/Mexico trial33
- 86.9% (95% CI: 73.7–93.5) in the United Kingdom trial.32
A phase II trial conducted in South Africa included more than 4,000 participants and provided data on vaccine efficacy against the Beta variant of SARS-CoV-2.31 Vaccine efficacy among HIV-negative adults was 60.1% (95% CI: 19.9–80.1) overall, and specifically against the Beta variant was estimated at 51% (95% CI: 0.6–76.2).
The significant difference in vaccine efficacy estimates between the United States/Mexico and United Kingdom trials and the South African trial has been attributed to the prevalence of the Beta variant in South Africa during the study period. However, other factors cannot be excluded
People aged ≥65 years
Vaccine efficacy was similar in younger and older age groups:
- age 18–64 years – 89.8–91.5% (95% CI: 79.7–95.5)32,33
- age ≥65 years – 88.9% (95% CI: 20.2–99.7).32
Children aged 12 to 17 years
A study is ongoing that involves adolescents aged 12 to 17 years. These adolescents received the same formulation of Novavax that is authorised for use in adults aged 18 years and older.
Among 1,799 trial participants aged 12 to 17 years without evidence of previous SARS-CoV-2 infection, Novavax was 79.5% effective (95% CI: 46.8–92.1) at preventing laboratory-confirmed symptomatic COVID-19 from day 7 after dose 2 (with an interval of 3 weeks between doses). This was based on 6 observed cases among 1,205 adolescent Novavax recipients compared with 14 cases among 594 placebo recipients. All cases were reported between June and September 2021. Of these 20 COVID-19 cases, viral sequencing was available for 11 cases (3 out of 6 in the Novavax group and 8 out of 14 in the placebo group). All viruses sequenced were the Delta variant. The resultant vaccine efficacy against the Delta variant was 82.0% (95% CI: 32.4–95.2). There were no cases of severe COVID-19 in either arm, so efficacy could not be determined against this outcome.35
In the trial in adolescents aged 12 to 17 years, the presumed protective efficacy was assumed through immunobridging – that is, the demonstration of an equivalent or better immune response in adolescents aged 12 to 17 years than the immune response in young adults aged 18 to 25 years, where efficacy has previously been shown against the ancestral strain. Neutralising antibody titres after 2 doses among 390 participants aged 12 to 17 years who received Novavax were comparable to those observed in 416 trial participants aged 18 to 25 years who received 2 doses of Novavax,35 with a ratio of 1.46 (95% CI: 1.25–1.71).36 These neutralising antibody responses were measured against the wild-type SARS-CoV-2 strain, not the Omicron variant of concern. The proportion achieving seroconversion was also similar (98.7%).35
People with specified medical conditions
Vaccine efficacy was similar in people with stable chronic conditions and in those without these conditions:32,33
- with stable chronic conditions – 90.8–90.9% (95% CI: 70.4–95.9)
- without stable chronic conditions – 89.1–89.9% (95% CI: 76.2–95.6).
There are limited data on the safety and immunogenicity of Novavax in people with immunocompromise. In the South African phase II trial, among 2,684 participants who were seronegative at baseline, 6% were HIV positive. When including all participants, vaccine efficacy was 49.4% (95% CI: 6.1–72.8). When HIV-positive participants were excluded, vaccine efficacy was 60.1% (95% CI: 19.9–80.1).34 Neutralising antibody geometric mean titres were comparable in HIV-positive and HIV-negative participants.
Co-administration with influenza vaccine
A small sub-study (n = 431) of the United Kingdom phase III trial assessed the impact of co-administering the first dose of Novavax or placebo with influenza vaccine.37 For people aged 18–64 years, vaccine efficacy against laboratory-confirmed symptomatic COVID-19 was not significantly lower in the co-administration group, estimated at 87.5% (95% CI: –0.2 to 98.4) in the co-administration group, compared with 89.8% (95% CI: 79.7–95.5) in the main study who received Novavax alone. SARS-CoV-2 binding antibody responses were approximately 0.6-fold lower in participants who received the co-administered vaccines compared with those who received Novavax alone. There were no significant differences in the immune responses to influenza vaccines between the groups. It is not yet known whether the impact of co-administration on immunogenicity translates to any difference in clinical protection or duration of protection against COVID-19.
Vaccine effectiveness in post-licensure studies
The effectiveness of COVID-19 vaccines has been studied in national vaccination programs since late 2020. Over this time, the distribution of variant strains in the country of study and during the period of study may have changed. This is a key consideration when interpreting results of vaccine effectiveness studies.
Some key findings from selected major studies on effectiveness of the vaccines currently available in Australia are summarised below. Results of other studies were generally consistent with these findings.
Vaccine effectiveness data for children under 12 years of age are not yet available. Data are expected in the coming months.
Vaccine effectiveness data for Novavax are not yet available.
Vaccine effectiveness against the Omicron variant
For the Omicron variant, all current ancestral-strain-based COVID-19 vaccines have lower immunogenicity after 2 doses. Neutralising antibody titres against Omicron are multiple-fold lower than against other variants, including Delta and the ancestral strain. However, a third dose of an mRNA COVID-19 vaccine resulted in neutralising antibody titres against Omicron that were greater than those after 2 doses against the Delta variant. Higher levels of T-cell protection markers were also seen in people who had 3 vaccine doses.38
Vaccine effectiveness against the Omicron variant is lower than for other variants after 2 doses of any of the ancestral strain-based COVID-19 vaccines used in Australia.39 However, a level of protection against symptomatic disease and severe outcomes is retained within the first few months after a second vaccine dose.40 A third vaccine dose has been shown to restore vaccine effectiveness against both Omicron infection and symptomatic COVID-19 disease.39-41
Most immunogenicity studies have shown a trend towards BA.4/5-based vaccines inducing higher neutralising activity against Omicron subvariants (including BQ.1 and XBB) than original vaccines.16,18,42-45 Others suggest the neutralisation response is similar between BA.4/5-based vaccines and original vaccines.46,47
Initial vaccine effectiveness studies indicate that a booster dose (fourth dose) with a bivalent Omicron-containing vaccine has estimated effectiveness against hospitalisation of 57% to 81% compared to not having a booster.1,2,48-50
ATAGI continues to monitor clinically significant variations in the efficacy or effectiveness of different vaccines against emerging strains.
Vaccine effectiveness over time
Several observational studies examine the post-licensure effectiveness of the COVID-19 vaccines registered in Australia in different populations in different countries. Overall, these studies showed that vaccine effectiveness of the original formulations against infection waned over about 4 to 6 months after completing the 2-dose primary schedule. These studies used varying study designs, and some stratified analyses by age group, vaccine brand, the presence of underlying risk conditions and infection due to different virus variants (e.g. Delta compared to Alpha).
Across these studies, vaccine effectiveness in the pre-Omicron era against more severe outcomes of COVID-19 (such as hospitalisation, ICU admission and death) appeared to be maintained with little or no decline over time up to 6 months.51-56 However, vaccine effectiveness against any PCR-confirmed infection (asymptomatic and symptomatic) and symptomatic infection (any COVID-19) decreased over time.55,57 The estimated decline in effectiveness against any infection due to the Delta variant in 4–6 months after 2 doses of Pfizer original formulation was 20–40%.55,57 The pattern of waning varied between individual vaccines. The decline in effectiveness over time against any PCR-confirmed SARS-CoV-2 infection has been associated with a reduced protective effect of vaccine in preventing virus transmission from vaccinated people.53,58,59
Data suggest that the vaccine effectiveness of BA.1-based bivalent booster vaccines is similar to ancestral-based booster doses, but potentially with slower waning of protection.49,60
Evaluation of vaccine effectiveness may be confounded by changes over time in public health and social measures, such as mask wearing, social distancing and travel. There may also be differences between vaccinated and unvaccinated people in how they adhere to these measures. This emphasises the importance of evaluating the entire body of evidence, and not just relying on single study outputs.
Vaccine effectiveness against SARS-CoV-2 transmission
Vaccination can help reduce the onward transmission of Omicron subvariants by two means: preventing infection of a close contact and reducing the likelihood that a person who becomes infected transmits the virus to another person, despite vaccination.
A review by the UK Health Security Agency found that vaccines provide some protection against infection for up to 6 months after a dose (0–30%).61 They further report that there may be a small additional benefit in reducing onward transmission from a vaccinated person who becomes infected.61
Evaluation of vaccine effectiveness against transmission may be confounded by changes over time in the vaccine formulations used, the predominant circulating variants, and levels of hybrid immunity within a community. Changes in public health and social measures, such as mask wearing, social distancing and travel, can also alter study results. This emphasises the importance of evaluating the entire body of evidence, and not just relying on single study outputs.
Vaccine effectiveness in older adults
In a single-centre case–control study in Bristol in the United Kingdom,62 vaccine effectiveness against hospitalisation among adults aged ≥80 years from 14 days after dose 1 was 71% (95% CI: 36–95) for AstraZeneca and 79% (95% CI: 47–93) for Pfizer original formulation.62
Other studies in the United Kingdom have reported the effectiveness of a first dose of either Pfizer original formulation or AstraZeneca at 76% (95% CI: 68–82) against overall SARS-CoV-2 infection in people aged ≥75 years and 81% (95% CI: 65–90) against hospitalisation in people aged ≥80 years.63-65 Among long-term care facility residents aged ≥65 years, vaccine effectiveness against PCR-confirmed SARS-CoV-2 infection (with or without symptoms) was estimated to be 62% (95% CI: 23–81) with no difference between AstraZeneca and Pfizer original formulation.65
A test-negative study in Ontario, Canada, included more than 300,000 participants. It was conducted from 14 December 2020 to 19 April 2021, when the Alpha variant was predominant in Ontario. Effectiveness for the mRNA vaccines (Pfizer and Moderna original formulations) against PCR-confirmed symptomatic disease in adults aged ≥70 years was 40% (95% CI: 29–49) ≥14 days after dose 1 and 94% (95% CI: 87–97) ≥7 days after dose 2.66
Waning of vaccine effectiveness has also been observed in older adults. For older adults (≥65 years old), the peak effectiveness after dose 2 was somewhat lower than younger adults.52,67
Vaccine effectiveness in people who are immunocompromised
There are many causes and varying degrees of immunocompromise. The risk of COVID-19 will vary according to:
- the number and type of underlying conditions
- medical management
- other factors.
Vaccine effectiveness studies suggest that immunocompromising conditions may be associated with a reduction in protection against COVID-19 compared with immunocompetent individuals. However, this finding has not been consistently demonstrated and these studies have some limitations. Overall, vaccine effectiveness against COVID-19 was around 70% to 90% in people who are immunocompromised,68-71 compared with 84% to 94% in the general population.
One study by Whitaker et al.71 examined both Pfizer original formulation and AstraZeneca in the United Kingdom to 13 June 2021. In a general immunocompromised population at least 4 weeks after 2 doses of vaccine, vaccine effectiveness against medically attended PCR-confirmed COVID-19 was estimated as 73.0% (33.9% to 89.0%) for Pfizer original formulation, and 74.6% (18.7% to 92.1%) for AstraZeneca.
Vaccine effectiveness studies70,71 in immunocompromised people confirm that it is essential to receive 2 doses of a COVID-19 vaccine, as protection may be suboptimal after a single dose. In partially vaccinated people who are immunocompromised, estimates of vaccine effectiveness range from 4% to 43%.70-72 These studies were conducted before the Delta variant emerged and may reflect effectiveness against older strains.
In the period of Omicron variant circulation, studies show that protection against infection after 3 doses of Moderna original formulation was estimated as 29.4% (95% CI: 0.3–50.0) in people who are immunocompromised, compared with 70.5% (95% CI: 68.6–72.4) in immunocompetent people.73 Protection against hospitalisation after 3 doses (primary course) in people who are immunocompromised was 60% (95% CI: 41–73).74
In people with higher degrees of immunosuppression, geometric mean titres of antibodies after vaccination are generally lower than in the general population. This includes people with solid organ transplant and haematological malignancies75-80 and people undergoing B cell depleting therapies (anti-CD20 monoclonal antibodies).81-83
It is difficult to predict the level of vaccine protection against asymptomatic infection, symptomatic infection, hospitalisation and severe disease based on immunogenicity data. This is because there is no clear correlate of protection from immunogenicity data.
Vaccine effectiveness in pregnant people
Evidence of good vaccine effectiveness of mRNA COVID-19 vaccines in pregnant women is also emerging. A retrospective cohort study that included 15,060 pregnant women in Israel, including 7,530 who received Pfizer original formulation, estimated effectiveness against PCR-confirmed SARS-CoV-2 infection from ≥28 days after vaccination to be 78% (95% CI: 57–89).84
Booster vaccine effectiveness
Early vaccine effectiveness data from 2 studies suggest that bivalent original/Omicron BA.4/5 formulations (Pfizer or Moderna) have some advantage over original formulations in preventing hospitalisation and death:
- 61.8% (95% CI 48.2 to 71.8) versus 24.9% (95% CI 1.4 to 42.8)2
- 80.5% (95% CI 69.5 to 91.5) versus 64.9% (95% CI 57.7 to 72.2), both relative to not receiving a second booster.1
First booster dose
Israel has progressively implemented a booster vaccine program using Pfizer original formulation in the general population aged ≥16 years since July 2021. Data from Israel suggest that a booster dose was effective at reducing infection (in eligible people of any age), severe disease (in people ≥40 years) and death (in people ≥60 years) compared with non-boosted people at least 5 months after their second dose.85-87 Limitations are that the data are from only a short observation period after the booster and are preliminary.
One study demonstrated an incremental protective effect with a booster dose of Pfizer original formulation at least 5 months since the previous dose among adults aged ≥60 years in the very short term (within 12–25 days after the booster dose). The study reported a >10 times lower rate of COVID-19 and severe COVID-19 among people who had a booster than in people who did not have a booster.86 A recent extension of this study showed a further protective effect of a Pfizer original formulation booster dose by age, given at least 5 months since the previous dose, among people aged ≥16 years.86 Compared with the non-booster group, the rate of PCR-confirmed infection in the booster group was:
- 12.4 times lower for people ≥60 years of age
- 12.2 times lower for people aged 50–59 years
- 9.7 times lower for people aged 40–49 years
- 8.8 times lower for people aged 30–39 years
- 17.6 times lower for people aged 16–29 years.
The rate of severe COVID-19 was 18.7 times lower for people aged ≥60 years, and 22.0 times lower for people aged 40–59 years. The rate of death due to COVID-19 was 14.7 times lower for people aged ≥60 years in the booster group compared to the non-booster group.86
Another study from Israel (using 2 different methods) found a relative vaccine effectiveness within 14–20 days after a booster dose of Pfizer original formulation of 70–79% against PCR-confirmed SARS-CoV-2 infection among people aged ≥40 years compared with people who had a 2-dose primary vaccination and no booster.88
Waning after first booster dose
Evolving evidence based on early vaccine effectiveness data and analysis of antibody levels after the first booster dose suggest there is gradual waning of immunity against the Omicron variant.73,89-91 This is most prominent for vaccine effectiveness against symptomatic infection, which declines from 60–75% at 2–4 weeks after a booster dose of either Pfizer or Moderna original formulations to 25–40% from 15 or more weeks after the booster in data from the UK.92 Vaccine effectiveness with any vaccine against hospitalisation commences at approximately 90% after a first booster dose and wanes to approximately 60% by 8 months compared to unvaccinated individuals.
Data from Qatar show that effectiveness against severe disease remained at >90% after 7 weeks or more after the first booster, although this was in a relatively younger population and may not be directly comparable.89
Early pre-print data suggest that the benefit of first booster doses in preventing onward transmission in breakthrough cases of Omicron may be substantially less than Delta and may be short-lived.93,94
Additional booster doses
Limited data from Israel and Canada suggest that people aged ≥60 years who received an additional booster dose of Pfizer original formulation or Moderna original formulation at least 3 months after the first booster were 40–76% less likely to have severe illness with COVID-19.95,96
UK data shows that a second booster (fourth dose) provides approximately 50% greater protection against hospitalisation, compared with the protection people otherwise have at 6 months or more after their third dose. The extra protection wanes over time, from 50% at 0 to 3 months after the fourth dose to 25% at 4 to 6 months afterwards.49
Another study in younger people aged ≥18 years showed the incremental protection from an additional booster dose to be limited and less certain. Those who received an additional booster dose were 11–30% less likely to be infected and 31–43% less likely to have symptomatic disease than those who had received only one booster. However, estimates were imprecise due to small numbers of infected people.97 Up to 30% of second booster recipients who had breakthrough infection were asymptomatic and their virus levels were no different from people who received only one booster. The role of an additional booster dose in reducing onward transmission of virus is less certain in this age group.97
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