This section of the COVID-19 chapter reflects the development of the COVID-19 vaccines and the changing behaviour and variants of the SARS-CoV-2 infection during the COVID-19 pandemic. Further data is emerging. There is much heterogeneity in the immunity of different populations, many people have hybrid immunity to the wild-type infection as well as a range of booster doses, which make effectiveness measures challenging. Overall, COVID-19 vaccines continue to perform very well against severe disease and mortality, and in the short term can help to prevent symptomatic illness and infection.
mRNA COVID 19 vaccine – Comirnaty (Pfizer/BioNTech)
Immunogenicity
Before the phase III efficacy studies were conducted in 2020, immunogenicity was a key indicator in the early-phase clinical trials of COVID‑19 vaccines. Comparable antibody responses were seen for the different doses of mRNA-CV vaccine formulations (30µg, 10µg or 3 µg) for each age group’s primary series.[47,48,49] The only group with lower antibody responses were older people (aged 55–85 years) but had higher average neutralising antibody levels than those who had SARS-CoV-2 infection.[50] Virus neutralising antibody responses measured the killing of live SARS-CoV-2 and/or pseudovirus in cell culture, and humoral responses were compared with human convalescent sera collected from patients who had recovered from COVID‑19. The initial phase I and II clinical trials evaluated two vaccine candidates (BNT162b1 and BNT162b2) in adults. Both induced dose-dependent neutralising antibody titres similar or higher to the titres in convalescent sera.[50]Similar immunogenicity was shown for mRNA-CV (30µg) between those aged 12–15 years and those aged 16–25 years; neutralising antibody responses were generally higher in the younger adolescents (geometric mean ratio (GMR) 1.76; 95% CI 1.47–2.10).[47] The immunogenicity of mRNA-CV (10µg) in 264 children aged 5–11 years was similar to that seen in young people aged 16–25 years given mRNA-CV (30µg).[48] At one month after two doses given 21 days apart, the neutralising antibody geometric mean ratio was 1.04 (0.93–1.18) when comparing the child and young adult titres. Similarly, the immune response in children aged 6 months to 4 years receiving three doses of mRNA-CV (3µg) was non-inferior to that seen in adults aged 18–25 years receiving mRNA-CV (30µg): ages 6-23 months GMR was 1.19 (1.0–1.43) and ages 2–4 years GMR was 1.30 (1.13–1.50).[49]
During 2022, evolving SARS-CoV-2 variants became more immune evasive to neutralising antibodies and higher levels of antibody were required to prevent infection. This was particularly evident in older people and those with comorbidities that affected the immune response. This evasion of the immune response was circumvented by offering booster doses. Bivalent mRNA-CV (15/15 µg) vaccines that express both the original SARS-CoV-2 spike protein and that of the omicron variants (BA.1 and BA.4-5) have been developed to help alleviate any immune evasion. SeemRNA COVID-19 vaccine – booster dosesdata below.
Efficacy – clinical trial data
Efficacy of 30µg mRNA-CV (BNT162b2) was assessed in the phase III component of a large, clinical trial in which 43,448 participants aged 16–85 years across six countries during 2020 were randomised to receive vaccine or saline placebo, with a primary series of two doses given 21 days apart.[51] Interim data, based on the early SARS-CoV-2 variants, indicated a very high efficacy against symptomatic PCR-confirmed COVID-19 of 94.8percent (95% CI: 89.8–97.6 percent) and across all subgroups.[51] Efficacy in younger age groups was also high. For adolescents aged 12-15 years vaccinated with two doses of mRNA-CV (30µg) efficacy of 100 percent (95% CI 75.3–100) was observed against symptomatic COVID-19 in 2020/2021.[47] A lower dose vaccine, mRNA-CV (10µg) showed efficacy of 90.7 percent (95% CI 67.7–98.3) against symptomatic COVID-19 was seen from seven days after dose two in 1,305 children aged 5–11 years.[48]
Due to a limited number of cases, vaccine efficacy is difficult to predict (as shown with wide confidence intervals) for mRNA-CV (3µg) in younger children. Vaccine efficacy against symptomatic COVID-19 of 75.5 percent (95% CI -370.1 to 99.6 percent) was shown from seven days after dose three in 386 children age 6–23 months (with one case) and compared with 184 children who received placebo (two cases); and in 606 children aged 2–4 years (two cases), vaccine efficacy was 82.3 percent (-8.0 to 98.3 percent) when compared with placebo given to 280 children (five cases). Combined for both ages, vaccine efficacy of 80.4 percent (14.1–96.7 percent) was reported during a period of Omicron prevalence in the US.[49,52] For the reasons detailed above, vaccine has not been recommended in younger age groups (0–4) in New Zealand unless they are immunocompromised.
Effectiveness of primary course – real-world experience
At the start of the COVID-19 immunisation programmes in late 2020/early 2021, mRNA-CV (30µg) was demonstrated to be highly effective at preventing severe COVID-19 and COVID-19-related death, in line with efficacy observed during clinical trials.[53] In the UK, a significant reduction in symptomatic COVID-19 and a reduction in severe disease was observed In older adults aged 70 years or over. At day 14 after a second dose (given 12 weeks after dose one), vaccine effectiveness reached 89 percent (85–93 percent).[54]
Effectiveness of mRNA-CV against symptomatic COVID-19 caused by the Delta variant was reduced in comparison with previous variants (ranging from around 78–93 percent),[55] but the vaccine remained highly effective against hospitalisation (73–94 percent), severe disease and death (80-97 percent) in a range of groups.[56] The risk of infection with Delta was also significantly lower in fully vaccinated compared with unvaccinated individuals (hazard ratio 0.35; 95% CI 0.32–0.39).[57]
As the Delta variant emerged from mid-2021, effectiveness against symptomatic COVID-19 reduced (ranging from around 78–93 percent),[55] but the vaccine remained highly effective against hospitalisation (73–94 percent), severe disease and death (80-97 percent) in a range of groups in the UK.[54] Subsequently, the effectiveness of the two-dose primary series against Omicron variant was found to have rapidly waning antibody levels and booster doses were required to help prevent symptomatic infection and reinfection (see below).
In adolescents aged 12–17 years in Arizona, interim effectiveness against Delta variant SARS-CoV-2 infection, irrespective of symptoms, was estimated to be 92 percent (95% CI 79–97 percent).[58] A test-negative case-control study in the US showed vaccination with mRNA-CV (30µg) to be protective against PIMS-TS in adolescents aged 12–18, with an estimated effectiveness of 91 percent (95% CI 78–97 percent), a median of 84 days (range 52–122) after vaccine dose two.[59]
Vaccination with mRNA-CV in pregnancy reduces the risk of severe COVID-19 and provides passive immunity to the infant for the first few months of life.[60,61,62]
Adjuvanted recombinant COVID-19 vaccine – Nuvaxovid (Novavax)
Immunogenicity
Like that seen with mRNA vaccines, two doses of rCV induce a robust neutralising antibody immune response in adults aged 18-59 years and those age 60-84 years. The older participants had lower antibody titres of anti-spike protein IgG or wild-type neutralising antibody than the younger group. In clinical trials conducted during 2020 and early 2021 in the US and Australia,[63] two doses of adjuvanted rCV were immunogenic in adults aged 18–59 years and 60–84 years. At 14 days after two doses given 21 days apart, neutralising antibody levels in both groups were higher than those in a panel of convalescent sera and all participants who received rCV seroconverted. At total of 1,283 participants were randomised 1:1:1:1 to receive one or two doses of vaccine (5 µg spike protein), a higher dose (25 µg) or placebo, and were stratified by age.[63]
Coadministration with influenza vaccines
Coadministration with influenza vaccine was investigated in a small phase I/II sub-study in UK hospitals. Around 400 participants were randomised to receive rCV and inactivated quadrivalent influenza vaccine for those aged 18–64 years or adjuvanted trivalent influenza vaccine for those aged 65 years or over, or rCV alone. Immunogenicity showed no change in the response to influenza vaccine but a reduction in antibody response to SARS-CoV-2. There was no difference in the seroconversion rates. Although the anti-spike protein IgG responses were 0.6-fold lower in the groups that received both vaccines, when post-hoc analysis of efficacy was considered, this reduction was not suggested to be clinically meaningful and in the younger age group, the anti-spike antibody levels were three-fold greater than found in convalescent serum.[64]
Efficacy – clinical trial
Data from two phase III clinical trials of adjuvanted rCV gave overall vaccine efficacy of 90 percent (95% CI 82.9-94.6 in PREVENT-19 study in US/Mexico and 80.2-94.6 percent in UK trial) against symptomatic COVID-19 from at least seven days after dose two.[65,66] By age group, in approximately 10,000 vaccinated and placebo participants in the UK (randomised 1:1), vaccine efficacy against COVID-19 in those aged 18-64 years was 89.8 percent (79.7-95.5) versus 88.9 percent (20.2-99.7) in approximately 4,000 participants aged 65– 84 years.[66] In a subgroup of approximately 6,000 participants with coexisting illness, vaccine efficacy was 90.9 (70.4-97.2).[66] These clinical trials were conducted during late 2020 and early 2021, against predominantly Alpha not Delta or Omicron variants.
Following the completion of the placebo-controlled portion of a phase III clinical trial in the UK, vaccine efficacy of 82.7 percent (95% CI 73.3–88.8 percent) against COVID-19 was reported from 7 days to up to 7.5 months (median 4.5 months) after vaccination with rCV (24 cases vaccinated and 134 cases who received placebo out of 13,989 participants). Vaccine efficacy against severe COVID-19 was 100 percent (17.9–100 percent). Protection gradually decreased after 6 months indicating a need for a booster dose.[67]
Effectiveness – real-world
This vaccine has only been recently approved for use and real-world effectiveness is beginning to be evaluated. There is no published effectiveness data to date.
Duration of immunity and booster doses
A decline in vaccine effectiveness was observed against SARS-CoV-2 infection and mild disease, particularly with emerging Omicron variants, but protection against severe disease has been maintained and enhanced with the use of booster doses for around 6–9 months, at least.[68,69] It is unclear how long-lived immunity is following immunisation or natural infection. Further data is awaited, particularly with the emergence of more infectious variants and greater number of people infected with wild-type virus. Waning in neutralising antibody levels was correlated with predominantly mild breakthrough infections in health care workers.[70] The greatest waning is observed in those aged over 65 years and those aged 40–64 years with underlying medical conditions compared with healthy adults.[71] The UK Health Security Agency reported that vaccine effectiveness against symptomatic infection was significantly lower against Omicron than Delta variant, such that by 15 weeks after two doses of mRNA-CV vaccine effectiveness had declined to between 34–37 percent. At more than 25 weeks after two primary doses, mRNA-CV vaccine effectiveness was 25–35 percent against hospitalisations due to Omicron variant.[68] Although neutralising antibody levels wane dramatically,[72] and lower levels are less effective against the emerging variants such as Omicron lineages, T cell responses and memory are maintained in vaccine recipients (for mRNA-CV and rCV).[73,74,75] and the rate of disease is reduced.
mRNA COVID-19 vaccine – booster doses
To prolong protection many countries introduced a booster dose after the primary course. Booster dose programmes were accelerated following the emergence of the Omicron variant from late 2021, including in New Zealand. Bivalent vaccines, with the mRNA expressing the spike protein of both the original ancestral and omicron variants, are being used as further additional doses to enhance protection against more immune evasive omicron variants.[75,76]
Booster doses of original monovalent mRNA-CV, given from five months after the primary course, were shown to reduce the rates of symptomatic COVID-19 by a factor of 11.3 (95% CI 10.4–12.3) and severe illness by a factor of 5.4 (4.8–6.1) in older adults aged from 60 years in Israel in 2021.[77] In the UK, a booster with original mRNA-CV increased effectiveness against hospitalisation to over 90 percent within two weeks but then declined to 75 percent after 10–14 weeks.[78] In Canada, vaccine effectiveness was significantly improved against symptomatic infection with Omicron variants, from <1% (-8 to 10 percent) to 61 percent (56–65 percent), by a booster dose of an mRNA COVID-19 vaccine given from 240 days after the second dose of primary course (with at least one dose of an mRNA vaccine). The booster dose was highly effective against severe outcomes of Delta or Omicron (98–99 percent and 87–98 percent, respectively).[69]
Further booster doses were recommended for certain groups (ie, fourth doses or fifth doses for those who have third primary dose). These additional doses increased both humoral and cellular immunity when given approximately seven months after a third dose booster in the UK. Anti-spike protein IgG titres were higher 14 days after a fourth dose than seen 28 days following the third dose (11–20 fold increase from day 0 to day 14 post fourth dose).[79] In an Israeli study, a fourth dose of mRNA-CV, given at least four months after the third dose to adults aged from 60 years, provided additional protection for at least six weeks and reduced the rate of severe COVID-19 by a factor of 3.5 (95% CI 2.7-4.6) compared with those who had received three doses, and reduced the rate of confirmed SARS-CoV-2 infection by a factor of two (1.0 –2.1) at four weeks. The study included over 1.2 million participants (1:1 received fourth and third doses).[80] There is marginal evidence that a fourth dose prevents infection in health care workers (given four months after dose three) – data from an open-label nonrandomised clinical trial in Israel, gave vaccine efficacy of 30 percent (-9 to 55) against Omicron infection and estimated 43 percent against symptomatic illness. Those who were infected were shown to have relatively high viral loads and likely to be infectious.[81]
Bivalent vaccines demonstrated improved immunogenicity and neutralising antibody activity against Omicron variants. In individuals who had received two doses in the primary series and a booster dose of monovalent mRNA-CV, a further booster dose with bivalent vaccine increased neutralising antibody titres against Omicron BA.4-5 by eight and ten times at one month post vaccination for all participants aged 18–55 and 56 years, respectively, who were seronegative or seropositive for SARS-CoV-2 infection at baseline. The greatest increase in antibody titres was seen in those who were seronegative at baseline (by around 20 times for both age groups). Pre-existing antibody titres were higher against the original reference strain than the BA.4-5 and BA.1 variants.[82] The bivalent booster dose was given to 95 adults aged 18-55 years (median time between doses: 10.9 months, range 5.6–12.8 months) and 102 participants aged 56 years and over (median time: 11.0 months, range 5.5–13.0 months).[82] Another study in nursing home residents and staff found that, although a marked increase in antibody was observed following a booster dose with bivalent mRNA-CV, T cells responses were not substantially augmented.[83]
A range of cohort studies in the US have demonstrated a relative improvement in effectiveness of booster doses against severe COVID-19 when bivalent mRNA-CV are given. This is especially for older adults who received two to four previous mRNA-CV doses several months prior.[84,85,86] Due to varying exposures to SARS-CoV-2 variants, timing since vaccine doses and in different populations, comparison between these studies is not possible. One study found that during September to November 2022, the vaccine effectiveness of a bivalent booster against hospitalisation or death due to omicron variants (BA4.6, BA.5., BQ.1 and BQ.11) was 36.9 percentage points (95% CI 12.6-64.3 percent) higher compared with a monovalent booster during May to August 2022 (using a baseline characteristics adjusted, time-varying hazard ratio for a single booster, first vs primary, second vs first booster, third vs second booster).[84] A test-negative designed study assessed hospital admission for COVID-19-like illness in 798 immunocompetent adults aged 65 years during September-November 2022. Among the confirmed COVID-19 cases, as defined by PCR-positivity, 21% were unvaccinated, 73% had received at least two doses of monovalent mRNA-CV at least 2 months prior to illness and 5% had received a bivalent booster dose 29 days (IQR 15-45) days prior to illness.[85] Compared with those who had received a monovalent 6-11 months and more than 12 months prior to illness onset, the relative effectiveness of a bivalent dose was 78 percent and 83 percent, respectively. There was no comparison with a subsequent monovalent dose, or a monovalent booster given within the previous 6 months.[85]
Early data from the Netherlands has estimated the efficacy of the XBB.1.5 mRNA-CV (30 µg) vaccine in adults aged 60 years and over to be around 70 percent against hospitalisation and ICU admission (95% CI 67-74 percent and 42.-88 percent, respectively) within the first two months of vaccination.[87] In the US, the overall VE against symptomatic infection was 58 percent (48-65 percent) up to 59 days after vaccination and 49 percent (36-58 percent from 60-119 days after vaccination.[87] Since the XBB.1.5 vaccine formulations were created, Omicron variants have evolved but are still demonstrating effectiveness against symptomatic disease and inducing a good neutralising antibody response against these newer variants, including BA.2.86 and JN.1.[87,88]
Adjuvanted recombinant COVID-19 vaccine– for booster doses
Immunogenicity of hom*ologous booster doses of rCV, evaluated during a secondary analysis of a phase II clinical trial, showed that antibody levels induced by the booster dose in healthy adults were higher than levels associated with efficacy in the primary response phase III trials.[72] In the phase II clinical trial, conducted in the US and Australia, a single booster dose was given approximately six months after two-dose primary course of rCV to 105 healthy adults aged 18 to 84 years. Immune responses at 28 days post booster (day 217) were compared with those at 14 days post dose two (day 35). Serum IgG GMTs increased 4.7-fold from day 35 to day 217 against ancestral SARS-CoV-2, and 4.1-fold in the neutralisation assay. Increases in functional ACE2 receptor binding inhibition were also observed from day 189 to day 217 (pre and post booster) against various variants, including a 24-fold increase against Delta and 20-fold increase against Omicron. Anti-spike IgG activity also showed improved titres against a range of variants, including 92.5-fold increase against Delta and 73.5-fold increase against Omicron.[72]
Mixed COVID-19 vaccine schedules
As part of the UK COV-BOOST study, all vaccines used as third-dose boosters demonstrated superior immunogenicity compared with control (except an inactivated virus COVID-19 vaccine in mRNA-CV primed group) as measured by anti-spike IgG and neutralising assays.[95] Participants aged 30 years or over with no history of laboratory-confirmed SARS-CoV-2 infection were given a booster dose at least 84 days post two doses of mRNA-CV (30µg Comirnaty) or at least 70 days post two doses of ChAd-CV. Participants received one of six vaccines including rCV, half dose rCV, ChAd-CV, mRNA-CV (Comirnaty), mRNA-CV (Spikevax) or MenACWY as control. Cellular responses in ChAd-CV primed individuals were better boosted by rCV than in those primed with mRNA-CV. Optimal timing of the dosing intervals remains unclear.[95]
