5. Coronavirus disease (COVID-19)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the Coronaviridae family and the Betacoronavirus genus. This enveloped, positive-strand RNA virus encodes four major structural proteins – spike (S), membrane (M), envelope (E) and a helical nucleocapsid (N). To enter host cells, the spike protein, which forms the characteristic crown-like (Latin: corona) surface structures, binds to the angiotensin-converting enzyme-2 (ACE2) receptor most frequently found on human respiratory tract epithelium.[1,2] SARS-CoV-2 was first detected in late 2019 in China and is thought to be a zoonotic disease of an unidentified origin.

As with most RNA viruses, mutations occur and variant strains of SARS‑CoV‑2 have been identified that have increased transmissibility, altered virulence, or have reduced the effectiveness of public health measures. WHO has classified genetic variants into three classes: variants of concern, variants of interest and variants under monitoring.[3] Emergence of new variants is monitored in New Zealand by ESR through whole genome sequencing of specimens taken from hospitalised cases and wastewater sampling. For more information on COVID-19 variants see the Ministry of Health website.

Coronavirus disease 2019 (COVID‑19) is caused by the SARS-CoV-2 virus, which infects the respiratory tract and is transmitted human to human primarily through respiratory droplets and aerosols. Documented transmission has also occurred through direct contact and rarely fomites (objects or materials that can carry infection).

The symptoms of COVID 19 range widely from asymptomatic infection or from a mild to severe respiratory tract infection and pneumonia, which can lead to severe inflammatory disease and respiratory failure. The most common symptoms of COVID-19 are like those of other common respiratory illnesses and include a new or worsening dry cough, sneezing and rhinorrhoea or nasal congestion, fever, sore throat, shortness of breath and fatigue. Unlike other respiratory viral infections, COVID 19 is frequently associated with a temporary loss of smell or altered sense of taste. Some cases have reported gastrointestinal symptoms including nausea, diarrhoea, vomiting and abdominal pain, headache, muscle aches, malaise, chest pain, joint pain, and confusion or irritability; these symptoms almost always occur with one or more of the common symptoms. For most cases COVID 19 is a mild disease, but some can develop more severe disease or exacerbation of comorbidities. As for influenza and other respiratory viruses, some of those with laboratory-confirmed infection remain asymptomatic.

In the early stages, it is difficult to distinguish COVID 19 symptoms from other common viral infections. The most reliable common diagnostic test has been detection of viral mRNA from a nasopharyngeal swab, using PCR assay and rapid antigen tests (RATs).

The incubation period is typically around two to five days (up to 14 days). Individuals may be infectious from up to two days before becoming symptomatic.[4] Unlike previous coronavirus outbreaks (SARS and MERS), transmission of SARS-CoV-2 can also occur before the onset of symptoms or from asymptomatic individuals.[5] Viral loads and infectiousness are highest immediately after symptom onset, and most transmission occurs in household settings.[6, 7]

It is currently unclear what or for how long protection is provided from previous infection with SARS-CoV-2. Neutralising antibodies have been detected and remained relatively stable between eight to 11 months after primary infection.[8, 9] Reinfection, including in vaccinated individuals, is likely due to being infected with different variants of SARS-CoV-2 when neutralising antibody immunity has waned. The risk of reinfection has been shown to be reduced in vaccinated individuals and hybrid immunity, of infection and vaccine reduces the risk of COVID-19 hospitalisation.[10, 11] This is likely to be highly variable so continued COVID-19 vaccination post infection is recommended as per the Schedule.

Commonly, children have mild or no symptoms of COVID-19 with a short duration of illness; symptoms typically include headache, fever, cough, and may include sore throat, nasal congestion, sneezing, muscle aches and fatigue.[12] Around one in five children with symptomatic COVID-19 present with gastrointestinal symptoms, such as nausea, vomiting, abdominal pain and diarrhoea.

The incidence of severe or fatal disease in children is significantly lower than in adults.[13] Children at higher risk of more severe disease are predominantly those living with pre-existing health conditions. These risk factors are prevalent in New Zealand children, particularly children of Māori and Pacific ethnicity.[14, 15] Pre-existing conditions associated with higher risk from COVID-19 in children include obesity, diabetes, asthma, cardiac and pulmonary diseases, immune disorders, metabolic disease, cancer, neurological, neurodevelopmental (in particular, Down syndrome [trisomy 21]) and neuromuscular conditions.[16, 17] A systematic review found children with comorbidities were 25 times more likely to have severe COVID-19 than those without (5.1 percent vs 0.2 percent) and have a 2.8 times higher relative risk of death.[17] Children who develop pulmonary complications (eg, pneumonia) have a similar progression of disease as seen in adults, requiring oxygen in hospital and in some cases corticosteroids and antiviral treatments.[18]

Risk factors for severe disease include older age, male, smoking,[19] obesity and chronic medical conditions, including diabetes,[20] cancer, chronic respiratory disease, cardiovascular disease, chronic kidney disease, hypertension, immunocompromise[21] and pregnancy (see below). Increased incidence is well documented in some ethnic groups but seems primarily related to prevalence of the risk factors listed above. Increasing age is the most important risk factor for severe disease, due to declining immune function and high prevalence of comorbidities. The highest risk group for severe illness and mortality is those aged over 70 years, although Māori and Pacific populations experience age-related risk at a younger age.

Health care workers

Patient-facing health care workers caring for patients with COVID‑19 are likely to be exposed to higher viral loads, placing them and their household members at greater risk of developing COVID‑19 than the general population.[22] However, the use of personal protective equipment (PPE) and other measures aimed at reducing nosocomial viral transmission have been shown to be effective, such that, when COVID‑19 is prevalent in the community, health care workers are more likely to catch COVID‑19 from an infected household member.[7]

Pregnancy

Pregnancy is not associated with increased risk of being infected with SARS-CoV-2, but it can increase the risk of severe disease and death compared with age-matched non-pregnant women.[23, 24,25,26] While the absolute risk of severe outcomes during pregnancy is low compared with absolute risk due to advanced age, the risk of hospital admissions is three times higher and the rate of ICU care for COVID‑19 has been found to be five times higher (relative risk 5.04; 95% CI 3.13–8.10) for pregnant women than for non-pregnant women.[25] Obesity, hypertension, asthma, autoimmune disease, diabetes and older age are also associated with severe COVID‑19 in pregnancy and postpartum.[27]

Infants born to those with COVID‑19 are at increased risk of preterm birth, particularly due to maternal COVID-19 severity leading to early induction, and neonatal ICU admission.[24, 27] Early studies do not suggest intrauterine transmission, but transmission during birth has been shown in around 3 percent of neonates.[28] Most neonatal infections are asymptomatic or mild, but around 12 percent experience severe disease with dyspnoea and fever as the most commonly reported signs.[29]

Post-acute COVID-19 sequalae or commonly called ‘long COVID’ is characterised by persistent symptoms lasting for more than three months and appears to affect around 10 percent of those infected, particularly those with at least five symptoms in the first week of illness.[30, 31,32] Post-acute manifestations include cardiovascular, pulmonary and neurological effects, including chronic fatigue, dyspnoea, specific organ dysfunction and depression.[33]

Long COVID-19 is not well described in children but appears to be less common, particularly under the age of 12 years, than in adults.[18,34,35,36]

For further information see the Health NZ webpage Long COVID.

Paediatric multisystem inflammatory syndrome

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS or MIS-C) is a rare, delayed complication of COVID-19 following largely asymptomatic SARS-CoV-2 infection in children and adolescents.[37, 38] PIMS-TS can occur approximately one month after symptomatic or asymptomatic SARS-CoV-2 infection affecting different parts of the body and usually presents as a fever, rash and abdominal pain, although in more severe cases, myocarditis and low blood pressure can occur.[39] Early diagnosis and appropriate treatment improve outcomes. Data from the US has shown that the risk PIMS-TS is highest in marginalised and ethnic minority groups.[40] The PAEDS network in Australian found that there was a lower risk for PIMS-TS in children when infected with the omicron variant, from a rate of 13 (95% CI 4-29) cases per 100,000 during the pre-delta period (March 2020 to May 2021) to 5 (4-7) per 100,000 during the delta period (June to December 2021) and 0.8 (0-1) per 100,000 during the omicron period to January 2022 to April 2022.[41]

SARS-CoV-2 was first identified in January 2020 following clusters of distinctive pneumonia cases observed in Wuhan, China during December 2019. This virus has genetic and clinical similarity to the coronavirus causing the severe acute respiratory syndrome (SARS) epidemic from 2002 to 2004. A public health emergency of international concern (PHEIC) was announced in late January 2020. By the time the COVID‑19 pandemic was declared by the World Health Organization (WHO) on 11 March 2020, there were 118,000 reported COVID‑19 cases and 4,291 associated deaths in 114 countries. The global death toll surpassed one million by late September 2020. Case numbers and death continued to increase, with a rapid peak in cases at the end of December 2021 due to the more infectious omicron variant. As of 8 November 2022, WHO reported over 6.5 million cumulative COVID-19 deaths.

See the WHO Coronavirus Disease (COVID‑19) Dashboard for the latest official data. Actual rates are expected to be considerably higher than officially reported rates, especially since milder infections may not be reported.

The infection-fatality rate, while still high particularly in the older age groups, has reduced since the start of the pandemic, partly due to changes in the prevalent variants but also due to public health measures that include vaccination, improved clinical recognition and management and the use of therapies of demonstrated value, such as dexamethasone and antiviral medications such as nirmatrelvir and ritonavir and molnupiravir.

The use of vaccines has reduced the global burden of COVID‑19 significantly. The first phase I clinical trial for a COVID‑19 vaccine commenced in March 2020 and the first public vaccination dose was administered in the United Kingdom on 8 December 2020. By late 2022, 11 COVID-19 vaccines had been granted emergency use listing or approval by the WHO.

In May 2023, the WHO declared an end to the PHEIC and moved forward to update its Strategic Preparedness and Response plan for 2023-2025 to transition from the emergency response to longer-term sustained COVID-19 protection, control and management.[42]

The first case of COVID‑19 was reported in New Zealand on 28 February 2020. Border restrictions were implemented on 16 March 2020 as cases numbers increased and clusters of transmission were identified. On 25 March 2020, New Zealand entered a nationwide lockdown (‘Alert level four’). With rapid contact tracing and the public health COVID-19 protection framework, the spread of SARS-CoV-2 was restricted during 2020 and 2021. Only 19 percent of the introductions of virus in 2020 resulted in ongoing transmission or more than one additional case.[43] Prior to the outbreak of the Delta variant in August 2021, most of the reported cases during 2021 were imported from overseas (over 95 percent from 1 January to 9 August 2021).

From 16 August 2021, the number of cases in New Zealand began to increase sharply due initially to the highly infectious Delta variant. From January 2022, when the more infectious Omicron variant entered the community, case numbers rose sharply but at this stage around 90 percent of the population aged from 12 years had been vaccinated with at least two doses of COVID-19 vaccine. Almost three years after the first case as of late February 2023, there were over 2.2 million cases recorded, over 26,000 hospitalisations, and 711 ICU admissions for COVID-19. There were 1,599 deaths coded with COVID-19 as the underlying cause, and the vast majority (96 percent) were aged over 59 years.

The COVID-19 Mortality Report in published September 2022 found that although COVID-19-attributed mortality was highest in older age groups, based on age-adjusted estimates, the risk of mortality for those aged under 60 years was 3.7 times higher for those Māori and 3.9 times higher for those of Pacific ethnicities than of European and Other ethnicities.[44] Comorbidity in those under the age of 60 years significantly increased the risk of mortality by 78 times, and explained 59 percent of the increased risk for Māori and 69 percent for Pacific ethnicities. Vaccination was shown to have a strong protective effect: after adjusting for age, sex, comorbidities and vaccination status (>2 doses), mortality risk was lowered but still 1.7 times higher in Māori and 1.9 times higher for Pacific compared with European/Other ethnicities.[44]

Emergence of new variants is monitored in New Zealand by ESR through whole genome sequencing of specimens taken from hospitalised cases and wastewater sampling. For current details on case demographics see COVID-19: Data and statistics and for the mortality report see COVID-19 Mortality in Aotearoa New Zealand: Inequities in Risk.

Clinical trials for COVID‑19 vaccine candidates began shortly after the pandemic was announced in March 2020. Between October to December 2020, the New Zealand Government signed advanced purchase agreements for four vaccine candidates, with purchase dependent on approval for use from the New Zealand Medicines and Medical Devices Safety Authority (Medsafe). This is an ongoing process and, therefore, the availability and eligibility for these different vaccines may change.

Medsafe continues to review for each COVID-19 vaccine candidate, examining clinical trial and post-marketing surveillance data. Provisional consent imposes conditions on these vaccines to restrict their use by health professionals according to the available data at time of approval. This approval status allows New Zealanders early access to medicines with significant unmet clinical need under the Medicines Act.

Funded vaccines

The mRNA-CV, Comirnaty, consists of messenger ribonucleic acid (mRNA) encoding the full-length spike glycoprotein of the SARS-CoV-2 virus, inside a lipid nanoparticle. The spike protein mRNA has an adjuvant effect, so no additional adjuvant is included. This original version was designated BNT162b2 in clinical trials conducted by Pfizer and BioNTech. This mRNA vaccine delivers the instructions for human cells to build the viral antigen, SARS-CoV-2 spike protein. The mRNA is temporarily protected from degradation by the lipid nanoparticle that also facilitates fusion with the recipient’s cell wall.[45,46]

The adjuvanted recombinant COVID-19 vaccine (abbreviation rCV), Nuvaxovid, contains recombinant SARS-CoV-2 spike protein in a stabilised prefusion conformation. The spike protein is produced by an insect cell-line that has been infected with an insect baculovirus expressing SARS-CoV-2 spike protein genes. Together, the purified spike proteins and the adjuvant matrix are formed into immunogenic nanoparticles. The proprietary adjuvant (Matrix-M) contains two purified saponin fractions from Quillaja saponaria (soapbark tree) which enhances the innate immune response and activates the production of neutralising antibodies and T and B cell immunity. The vaccine was designated NVX-2373 in clinical trials conducted by Novavax and is sponsored in New Zealand by Biocelect. 

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 (30 µg, 10 µg 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 (10 µg) in 264 children aged 5–11 years was similar to that seen in young people aged 16–25 years given mRNA-CV (30 µg).[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 (3 µg) was non-inferior to that seen in adults aged 18–25 years receiving mRNA-CV (30 µg): 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. See mRNA COVID-19 vaccine – booster doses data below.

Efficacy – clinical trial data

Efficacy of 30 µg 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 94.8 percent (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 (30 µg) 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 (10 µg) 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 (3 µg) 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 (30 µg) 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 (30 µg) 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 homologous 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]

mRNA COVID 19 vaccine – Comirnaty (Pfizer/BioNTech)

XBB.1.5 mRNA-CV (30 µg), for ages 12 years and over

This vaccine requires storage at ultra-low temperatures (-90°C to -60°C) and at this temperature has a shelf-life of 18 months. Store unopened vials (with grey cap) at +2°C to 8°C for up to 10 weeks within the 18 months shelf-life. Do not freeze. Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Store opened vaccine in vials at +2°C to 8°C for a maximum of 12 hours, or store vaccine drawn-up in syringe for a maximum of six hours at +2°C to 30°C. Discard any vaccine exceeding these times, accordingly. For further details, see also the IMAC COVID-19 information and factsheets available from immune.org.nz.

mRNA-CV (10 µg) for ages 5–11 years

This vaccine requires storage at ultra-low temperatures (-90°C to -60°C) and at this temperature has a shelf-life of 12 months. Store unopened, undiluted vials (with orange cap) at +2°C to 8°C for up to 10 weeks within the 12 months shelf-life. Do not freeze. Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Prior to use, once an undiluted vial is taken out of the refrigerator, allow time (up to 2 hours) for the vaccine to reach room temperature and to be diluted. Store diluted vaccine in vials at +2°C to 8°C for a maximum of 12 hours, or store vaccine drawn-up in syringe for a maximum of six hours at +2°C to 30°C. Discard any vaccine exceeding these times, accordingly. For further details, see also the IMAC COVID-19 information and factsheets available from immune.org.nz.

mRNA-CV (3 µg) for ages 6 months – 4 years

This vaccine requires storage at ultra-low temperatures (-90°C to -60°C) and at this temperature has a shelf-life of 12 months. Store unopened, undiluted vials (with maroon cap) at +2°C to 8°C for up to 10 weeks within the 12 months shelf-life. Do not freeze. Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Prior to use, once an undiluted vial is taken out of the refrigerator, allow time (up to 2 hours) for the vaccine to reach room temperature and to be diluted. Store diluted vaccine in vials at +2°C to 8°C for a maximum of 12 hours, or store vaccine drawn-up in syringe for a maximum of six hours at +2°C to 30°C. Discard any vaccine exceeding these times, accordingly. For further details, see also the IMAC COVID-19 information and factsheets available from immune.org.nz.

Adjuvanted recombinant COVID-19 vaccine – Nuvaxovid (Novavax)

Transport and store according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Store at +2°C to +8°C. Do not freeze. Protect vials from light. Unopened vials (with blue cap) have a shelf-life of up to six months. Opened vials should be used within 12 hours of first use. Vaccines should ideally be used within an hour of being drawn up. The maximum time the vaccine can be stored in a syringe is six hours when stored at +2°C to 25°C, and before the vial 12-hour expiry is reached, whichever is soonest. To ensure optimum use, in New Zealand, the vaccine is recommended to be always stored in the fridge and, where practical, doses are drawn up as required.

For further details, see also the IMAC COVID-19 information and factsheets available from immune.org.nz.

mRNA COVID‑19 vaccine – Comirnaty (Pfizer/BioNTech)

XBB.1.5 mRNA-CV (30 µg) for ages from 12 years (grey caps)

Individuals from the age of 12 years who have not previously received any doses of COVID-19 vaccine are recommended to receive a single dose of mRNA-CV (30 µg).

All individuals aged from 16 years are recommended a further dose after receiving a primary dose(s) of COVID-19 vaccine. See section ‎5.5.10 for additional dose recommendations.

Individuals who have started but not completed a primary course

Individuals aged 12 years and over who have not completed a primary course of any COVID-19 vaccine are recommended to be offered a dose of XBB.1.5 mRNA-CV (30 µg), given from 3 months after the first dose. It is considered off-label for XBB.1.5 mRNA-CV to be given sooner than 3 months after a previous dose of any COVID-19 vaccine, therefore, a prescription would be required if shorter spacing (from at least 3 weeks) is required.

mRNA-CV (10 µg) for ages 5 to 11 years (orange cap)

Two doses mRNA-CV (10 µg, orange cap) given at least 8 weeks apart to children aged from 5 years up to 11 years. In situations where the longer interval is not possible (eg, prior to planned immunosuppression, required for urgent international travel or at very high risk from exposure to SARS-CoV-2), give the second dose a minimum of 21 days after first.

For children who turn 12 years after their first dose, it is recommended to give an age-appropriate vaccine (ie, XBB.1.5 mRNA-CV (30 µg)) for the second or subsequent primary doses, maintaining a three-month gap between doses.

mRNA-CV (3 µg) for ages 6 months to 4 years (maroon cap)

A mRNA-CV (3µg, maroon cap) has been approved for use as a paediatric formulation in children aged 6 months to younger than 5 years in New Zealand. Three doses are given to individuals aged 6 months to under 5 years. It is recommended to administer dose two at least 21 days after dose one followed by dose three at least eight weeks after dose two.

The use of this vaccine is limited to young children who are at highest risk of severe disease if they were to catch COVID-19 such as those with severe immunocompromise (see section 5.5.8) or with complex and/or multiple health conditions (see the Starship website).

Children who start their course aged under 5 years need three doses even if they turn 5 years part way through their course. For children who turn 5 years after their first dose, it is recommended to give an age-appropriate vaccine (ie, mRNA-CV (10 µg, orange cap) for second or subsequent doses: dose two is given at least 21 days after first dose and dose three is given at least 8 weeks after previous dose.

The preferred vaccine for the Schedule is mRNA-CV, however, adjuvanted rCV can be offered (if not contraindicated, see section 5.6), where available, to individuals aged from 12 years who are contraindicated mRNA-CV or have experienced an adverse reaction to the first dose of mRNA-CV. It can also be offered to individuals who have declined mRNA-CV and would prefer an alternative vaccine. Individuals opting for this vaccine are recommended to discuss the benefit and potential risks of receiving this vaccine with a health professional. 

The following gives details of approved and off-label use of rCV.

• A (homologous) primary course two doses of rCV from age 12 years – no prescription is required.
• For a mixed (heterologous) primary course when a different COVID-19 vaccine dose was given previously – a further primary dose with rCV (if considered appropriate by a clinician, see section ‎5.5.10) is an off-label use and will require prescription from an authorised provider (under regulation s25 of the Medicines Act 1981).
• Additional dose(s) following any previous COVID-19 vaccine for individuals aged 18 years or older – no prescription required.
• Additional doses are not yet approved for ages 12–17 years.

Written consent is recommended when a prescription for any doses is required.

Vaccination should be offered regardless of an individual’s history of symptomatic or asymptomatic SARS-CoV-2 infection. As the duration of protection post infection is currently unknown, vaccination is recommended. Although, there are no specific safety concerns around giving mRNA-CV to individuals with a history of SARS-CoV-2 infection or symptomatic COVID-19, those who have had recent infection can experience more systemic reactogenicity after the first dose of mRNA-CV (see section ‎5.7.1).[96] Viral or serological testing is not required before vaccination.

A person aged from 5 years (or from age 6 months for special groups) who has had prior SARS-CoV-2 infection is recommended to complete the recommended course of mRNA-CV (or another COVID-19 vaccine, as available).

• For those completing the primary course, vaccination is recommended to be continued from three months after recovery from acute illness, or three months from the first confirmed positive test if asymptomatic.
• For individuals requiring additional doses after completing the primary series, vaccination is recommended to be continued as appropriate from six months after recovery from acute illness, or six months from the first confirmed positive test if asymptomatic.
• Based upon clinical discretion, where the individual is at very high risk of severe disease from reinfection and has not completed the recommended additional doses, vaccination can be shortened to a minimum of three months after SARS-CoV-2 infection and completed with the recommended spacing between doses.

For all other vaccines, vaccination can commence as soon as the individual is no longer acutely unwell.

As with all schedule vaccines, there are no safety concerns about giving mRNA-CV to those lactating. There is limited data to date around the use of adjuvanted rCV in lactation. 

Anyone who is pregnant or planning pregnancy is encouraged to be routinely vaccinated with mRNA-CV at any stage of pregnancy. The risk of an adverse outcomes from COVID-19 infection during pregnancy is significantly higher compared to age-matched non-pregnant adults (see section ‎5.2.2).[27] International evidence from large quantities of safety surveillance has found no safety concerns with administering mRNA-CV in any stage of pregnancy including no safety concerns of the infant.[97,98,99, 100] There is also evidence of antibody transfer in cord blood and breast milk which can offer protection to infants through passive immunity.[62,101,102,103] Infants born to those vaccinated in pregnancy have some protection from COVID-19-associated hospitalisation for up six months.[104]

Pregnant women with questions or concerns are encouraged to discuss them with their health professional. People who are trying to become pregnant do not need to avoid pregnancy after receiving mRNA-CV or rCV.

Those who are unable or do not wish to receive mRNA-CV, can receive rCV in pregnancy from age 18 years. There are no known safety concerns, but due to limited experience around the use of this vaccine in pregnancy, they should discuss the suitability of rCV for them with their health professional and written consent is recommended. For further advice around eligibility and prescribing, see the Health NZ website.

For information about additional doses in pregnancy, see section 5.5.10.

It is highly recommended that all eligible adults including the frail and elderly with comorbidities are offered vaccination against COVID-19, if there are no contraindications to its administration (see section 5.6.1), to provide protection for the individual as well as their community, especially when living in residential care facilities. 

It is recommended that all previously unvaccinated individuals from age 12 years to receive one dose of mRNA-CV (30 µg). Children aged 5–11 years are recommended two doses of paediatric mRNA-CV (10 µg) given at least 8 weeks apart. Pre-existing cardiac conditions, in general, are not regarded as precautions or contraindications to vaccination. This includes pre-existing rheumatic heart disease. Note that many cardiac conditions increase the risk from COVID-19 infection.

Individuals aged from 5 years with a history of pericarditis or myocarditis, unrelated to mRNA-CV, can have the vaccine once the condition is completely resolved, (ie, no symptoms and no evidence of ongoing cardiac inflammation). 

Infants and young children aged from 6 months to 4 years with complex congenital heart disease, acquired heart disease or congestive heart failure are recommended to received three doses of mRNA-CV (3 µg), dose two given at least 21 days after dose one and dose three given at least eight weeks later. For young children with a history of inflammatory heart disease, discuss with cardiologist/specialist paediatrician.

For those with a history of myocarditis and pericarditis related to mRNA-CV, seek specialist immunisation advice on a case-by-case basis to consider an appropriate alternative vaccine (eg rCV from age 18 years as an additional dose) or no further vaccination, and timing of any further doses. See section ‎5.6.2 for those who have myocarditis associated with mRNA-CV.

There are no safety concerns around administering mRNA-CV or rCV to individuals who are immunocompromised and/or receiving immunosuppressive agents. As with other non-live vaccines, the antibody response to these vaccines may be reduced and protection may be suboptimal but, it is likely to be adequate to protect against severe disease. It is recommended to discuss the optimal timing for vaccination with a specialist before the vaccine appointment for those who are severely immunocompromised. Ideally, vaccination should be conducted prior to any planned immunosuppression (see section ‎4.3.7).

It is important that all household members and other close contacts of immunocompromised individuals aged from 5 years are up to date with immunisations. Close contacts aged from 16 years should also receive an additional dose at least six months after any previous doses or SARS-CoV-2 infection. For additional doses, see section ‎5.5.10.

Individuals who are severely immunocompromised

Three primary doses of mRNA-CV (10 µg or 30 µg, as age-appropriate) are indicated for certain individuals aged from 5 years who are severely immunocompromised who are likely to have not responded adequately to the first doses (for children younger than 5 years, see note below). Serology is not recommended. A second and third primary dose is distinct from a booster dose or additional doses (for additional doses see section ‎5.5.10).

Preferably, a second dose is given eight weeks after dose one, and a third dose given a further at least eight weeks after the second dose. However, the timing also needs to consider current or planned immunosuppressive therapies. If the period of least immunosuppression is less than eight weeks, the vaccination can be given any time from three weeks after dose one and from four weeks after dose two. Where possible, delay the third dose until two weeks after the period of immunosuppression (in addition to the clearance time-period of therapeutic). If this is not possible, consider vaccination during a treatment ‘holiday’ or at a nadir of immunosuppression between doses of treatment.

These additional doses are currently considered off label and can only be offered with a prescription from an authorised prescriber with informed, preferably written, consent (under regulation s25 of the Medicines Act 1981). 

• Since XBB.1.5 mRNA-CV (30µg) is routinely recommended as a single dose for those aged 12 years and over, both of the additional primary doses are considered off-label (ie when given at three weeks and then eight weeks or less apart, respectively).
• If, for some reason, there is a delay of longer than 3 months in giving one of more of these additional primary doses, a prescription is no longer required but there is a risk that protection between doses will be suboptimal.
• For children aged 5 to 11 years, primary course of mRNA-CV (10µg) is a two-dose course; in this case, only the third dose at 8 weeks after dose two, this is considered off-label.

If a significant adverse reaction to mRNA-CV has occurred that contraindicates further mRNA-CV doses, then rCV may be considered for a third primary dose for those aged from 12 years (if not contraindicated) who are severely immunocompromised. This also requires prescription and written consent is recommended. It is recommended to seek advice from IMAC.

Note: For children aged 6 months to 4 years, three doses of mRNA-CV (3 µg, maroon cap) is available for those who are severely immunocompromised, including those given in Table 5.4, and for those who have complex or multiple health conditions that increase their risk from COVID-19 (see the Starship website), such as:

• chronic lung disease including bronchiectasis, cystic fibrosis, BiPAP for obstructive sleep apnoea (not asthma)
• complex congenital heart disease, acquired heart disease or congestive heart failure
• diabetes (insulin-dependent)
• chronic kidney disease (GFR <15 ml/min/1.73m²)
• severe cerebral palsy (or severe neurodisability including neuromuscular disorders)
• complex genetic, metabolic disease or multiple congenital anomalies for example trisomy 21/Down Syndrome
• primary or acquired immunodeficiency
• haematological malignancy and/or post-transplant (solid organ or HSCT in last 24 months)
• on immunosuppressive treatment including chemotherapy, high-dose corticosteroids, biologic agents or DMARDS.

Table 5.4 provides guidance on types of immunocompromise for which three primary doses are recommended for those aged from 5 years, and for children aged 6 months to 4 years with immunocompromise eligible for mRNA-CV (3 µg). For further information on corticosteroid indicative dosages and examples of non-corticosteroid agents considered immunosuppressive, see section below and Table 5.5.

Individuals from age 6 months who have undergone haematopoietic stem cell transplantation since their first course can be revaccinated with a three-dose primary course of a COVID-19 vaccine, plus additional doses as age appropriate (preferably with age-appropriate mRNA-CV).

Based on clinical discretion, if all scheduled doses have been completed prior to commencement of chemotherapy or solid organ transplant, a single further dose of mRNA-CV can be given.

Anyone aged 16 years or over who has not yet received an additional dose since completion of the primary course is recommended to receive a single dose of XBB.1.5 mRNA-CV (30µg), if not contraindicated. 

Certain individuals with severe immunosuppression are recommended to receive three primary doses (see section ‎5.5.8; this is part of the primary course and not the same as additional doses described in this section).

A dose of XBB.1.5 mRNA-CV (30µg) is available for all adults aged from 30 years and recommended for those aged from 12 years at increased risk of severe COVID-19, regardless of number prior doses received. This additional dose can be given at least six months after the previous dose of COVID-19 vaccine or at least six months after a recovery from acute COVID-19 illness or a positive SARS-CoV-2 test (see section 5.5.7).

Clinical discretion can be applied, case by case, when considering vaccination given less than six months after infection or previous dose. A shorter spacing of a minimum of three months may be appropriate for those individuals considered to be at very high risk of severe disease from COVID-19 re-infection. Spacing of at least six months is preferred.

Due to the risk from waning protection, those at highest risk from severe breakthrough COVID-19 are particularly recommended to have a dose of mRNA-CV (30 µg) XBB.1.5 to extend and provide broader protection. This includes:

• people of Māori or Pacific ethnicities aged 50 years and over
• all other individuals aged 65 years and over
• residents aged 16 years or over living in aged care and disability care facilities
• severely immunocompromised people who were eligible to receive three primary doses (see section ‎5.5.8) aged 12 years and over
• individuals aged 12 years and over who are eligible for influenza vaccination, including those:
  • who are pregnant (see Additional doses in pregnancy)
  • who have certain medical conditions that increase the risk of severe breakthrough COVID-19 illness (see Table ‎5.6 and section ‎5.5.8) 
  • who live with disability with significant or complex health needs or multiple comorbidities (see Table ‎5.6 and section ‎5.5.8)
  • who are severely obese (BMI ≥40 kg/m²) or severely underweight (BMI <16.5 kg/m²).

For further information see the Health NZ website. For underlying health conditions that increase risk for severe COVID-19 in adolescents see the Starship website. This list is not exhaustive and clinicians may use their judgement for conditions that are not listed.

Although an mRNA-CV is the preferred vaccine, rCV can also be used as an additional dose, if not contraindicated. A prescription is not required for individuals aged 18 years and over (except in pregnancy, Additional doses in pregnancy).

Vaccination with mRNA-CV or rCV is contraindicated for individuals with a history of anaphylaxis to any component or previous dose the same vaccine.

A definite history of immediate allergic reaction to any other product is considered as a precaution but not a contraindication to vaccination with COVID-19 vaccines (mRNA-CV or rCV). A slightly increased risk of a severe allergic response in individuals who have had a previous anaphylaxis-type reaction needs to be balanced against the risk of SARS-CoV-2 exposure and severe COVID‑19. These individuals can still receive a COVID-19 vaccines, if not contraindicated, and observation extended to 30 minutes after vaccination in health care settings, where anaphylaxis can be immediately treated with adrenaline.

Myocarditis or pericarditis

If myocarditis, myopericarditis or pericarditis occurs after a dose of mRNA-CV or rCV, defer further doses of COVID-19 vaccination. Seek specialist immunisation advice, on a case-by-case basis, to consider an appropriate alternative vaccine or no further vaccination, and about timing for further doses. Vaccination is not recommended for anyone with current active cardiac inflammation.

The risk of myocarditis following vaccination is not thought to be greater in children aged 6 months to 4 years than any other group, acknowledging that background rates of myocarditis from any cause in infants (aged under 1 year) are generally higher than in older children. There is no current evidence of a safety concern with this vaccine in young children or infants, overall.

Pregnancy

The preferred vaccine to be given in pregnancy is mRNA-CV. Those who are pregnant are advised to discuss the benefit and potential risks of receiving rCV in pregnancy with their health professional. There are no safety concerns should it be given inadvertently in pregnancy.

mRNA COVID 19 vaccine – Comirnaty (Pfizer/BioNTech)

Commonly reported responses to mRNA-CV (30 µg) during clinical trials and post-licensure surveillance are injection-site pain, headache, dizziness and fatigue; other responses included muscle aches, feeling generally unwell, chills, fever, chest discomfort, joint pain, nausea and axillar lymph node swelling. These occurred most often after dose two and in younger adults (aged 18–55 years), and within one or two days of vaccination. Most are mild or moderate in severity and are self-limiting.[51, 106] The responses to XBB.1.5 mRNA-CV given as a single primary dose or as an additional dose is expected to be similar compared to original mRNA-CV and bivalent mRNA-CV (15/15 µg) vaccines. No new adverse reactions have been identified in clinical trials and real-world usage.[107] Analgesia, such as paracetamol or ibuprofen (as appropriate), can be taken for pain and discomfort following vaccination. It is advisable to limit vigorous exercise if feeling unwell.

During clinical trials, the responses in children aged 5–11 years given paediatric formulation mRNA-CV (10 µg) were similar to those seen for the adult formulation mRNA-CV (30 µg) in those age 16–25 years. Generally, reactions were mild to moderate and short-lived. Pain at injection site was commonly reported (by over 70 percent) after dose one and two. Overall fewer children reported systemic reactions than seen after the 30 µg dose in adults, with fever, fatigue, headache, chills and muscle ache as the most common and more frequent after the second dose.[48] These responses were mirrored in reports to VAERS and V-safe after 8.7 million doses given routinely to children in the US.[108]

In clinical trials for paediatric mRNA-CV (3 µg), the most frequent responses seen in infants (aged 6–23 months) were irritability, decreased appetite, injection-site tenderness and redness, and fever; and in children aged 2–4 years, injection-site pain and redness, fatigue and fever. Less common responses included lymphadenopathy, diarrhoea, vomiting and nausea. Consistent with the clinical trial, systemic reactions were more frequently reported to V-safe in the US for infants (ages 6 months – 2 years) than those aged 3–5 years.[109]

See chapter 2 (section 2.3.3) for immunisation-stress related responses (ISRR).

Adjuvanted recombinant COVID-19 vaccine – Nuvaxovid (Novavax)

The most reported responses to rCV in clinical trials were injection-site tenderness and pain, headache, fatigue, myalgia, malaise, arthralgia, nausea and vomiting. These reactions were more common after dose two, lasting for one to three days, and occurred at higher incidence in younger age groups (less than 65 years).[66]

Breast screening and CT scans

Transient unilateral axillary adenopathy, a known response to vaccination, was particularly noted following vaccination with mRNA-CV due to the scale of the roll-out and age groups being immunised. Early estimates suggest that 12–16 percent of vaccine recipients experience axillary adenopathy after vaccination with mRNA-CV, starting one or two days after vaccination and which can persist for several weeks.[110, 111] Lymphadenopathy has also been commonly reported after additional doses of mRNA-CV.[112]

When attending breast screening appointments, including MRI scans and mammography, it is recommended that individuals advise the radiographer or doctor that they have received a COVID-19 vaccine recently. It is advised to monitor any lymph node changes that persist for longer than six weeks after vaccination.[110]

Likewise, individuals undergoing FDG PET/CT or MRI scans for cancer screening are advised to inform the radiologist or their oncologist that they have been recently vaccinated, or, if possible, to have COVID-19 vaccination at least two weeks before a scheduled scan or as soon as possible afterwards. Treatment should not be delayed.

Adverse events following immunisation (AEFIs) with the COVID-19 vaccines are being closely monitored during clinical trials and by post marketing surveillance. A dedicated COVID-19 vaccine AEFI reporting tool is available online from CARM (see section 1.6.3). Medsafe reports weekly on the AEFI reported to CARM after COVID-19 vaccinations (see the Medsafe website).

A list of adverse events of special interest (AESIs), including those previously associated with immunisation in general and with the individual vaccine platforms, was created by Safety Platform for Emergency Vaccines (SPEAC) in collaboration with the Coalition for Epidemic Preparedness Innovations (CEPI) and based on existing and new Brighton Collaboration case definitions. For further information, see the Brighton Collaboration website. Global pharmacovigilance and active safety monitoring systems continue to watch for both AESI and unexpected AEFI.

mRNA COVID 19 vaccine – Comirnaty (Pfizer/BioNTech)

Overall, no AESI signals were detected by the Vaccine Safety Datalink in the US up to 21 days after vaccination, following the administration of over 13 million doses of mRNA-CV (Comirnaty), however, subgroup analyses did find mRNA-CV to be associated with a slight increase in myocarditis and pericarditis in younger people (aged under 30 years).[113, 114]

Preliminary phase II/III clinical trial safety data reported lymphadenopathy in 64 (0.3%) vaccine recipients and six (<0.1%) placebo recipients (follow-up of up to 14 weeks after second dose of a subset of 18,860 participants who received at least one dose of mRNA-CV). Four vaccine-related adverse events were recorded (namely, shoulder injury related to vaccine administration, lymphadenopathy local to injection site, paroxysmal ventricular arrhythmia and right leg paraesthesia). No deaths were related to either the vaccine or the placebo.[51] During clinical trial follow-up to 1 February 2021, acute peripheral facial paralysis (Bell’s palsy) was reported by four vaccinated participants and none in the placebo group.[115] No safety signal has been detected for this condition as an AESI,[116] and safety monitoring is ongoing.

No vaccine-related severe adverse events were seen during the phase II/III clinical trial of mRNA-CV (10 µg) and mRNA-CV (3 g). In 1,518 children aged 5–11 years, lymphadenopathy was reported in ten (0.9 percent) of mRNA-CV (10 µg) recipients. Rashes, with no consistent pattern, considered related to the vaccination were observed in four participants; these were mild and self-limiting with typical onset seven or more days after vaccination. No differences were apparent in vaccine safety between the children who had baseline evidence of previous SARS-CoV-2 infection.[48] Following administration of approximately 8.7 million doses of mRNA-CV (10 µg) in children aged 5–11 years in the US, the majority of reports to VAERS (97.6 percent) were non-serious and 2.4 percent were serious. The most common non-serious reports were due to vaccine administration errors. Of the serious reports, 11 verified cases of myocarditis were reported to VAERS but no chart-confirmed myocarditis cases were reported through the Vaccine Safety Datalink in this age group.[108] Post-licensure surveillance is ongoing internationally.

Bivalent mRNA COVID-19 vaccines

Safety monitoring in the US was evaluated following of use bivalent mRNA-CV as a booster dose (approximately 14.4 million doses bivalent Comirnaty and 8.2 million doses of bivalent Moderna) given to those who had received at least two doses of monovalent original mRNA-CV.[107] Of the 5,542 VAERS reports, 34% of events were vaccine administration and handling errors and 95% non-serious AEFI. V-safe reports, from almost 211,959 participants aged at least 12 years who received age-appropriate bivalent booster doses, were consistent with those reported following monovalent booster doses. Most people were receiving their fourth or fifth COVID-19 vaccine dose and 98.3 percent received influenza vaccine at the same visit. Adverse events were less common and less serious than the health impacts associated with COVID-19 illness.[107]

Myocarditis and pericarditis

A small increase in incidence of myocarditis, myopericarditis and pericarditis has been observed following the second dose of mRNA-CV vaccination (40.6 cases per million doses in young males and 4.2 cases per million in young females, aged 12–29 years, decreasing to 2.4 and 1.0 per million, respectively, in men and women aged over 30 years).[117] Very rarely, myocarditis has also been report in boys aged 5–11 years after dose two in the US (reporting rate of 2.2 cases per million doses).[118] Most cases occur within 14 days of vaccination typically with full recovery after standard treatment and rest.[119, 120] A review of clinical records in the US observed the median time to onset for myocarditis was 3.5 days (interquartile range 3.0–10.8 days) after vaccination and a median of 20 days (range 6.0–41 days) for pericarditis.[120] Wider spacing between doses (ie, eight weeks) has been shown to significantly lower the risk of myocarditis in young adults in Canada.[121] Following 22.6 million doses of bivalent mRNA-CV given to individuals aged from 12 years in the US, three out of five cases of myocarditis and four cases of pericarditis reported to VAERS were medically verified. These early data confirm that myocarditis and pericarditis post vaccine dose is an extremely rare event and suggests that this rate is the same or lower than after the primary doses.[107]

Myocarditis and pericarditis are uncommon conditions considered to be associated with viral infection, including COVID-19. Recently vaccinated individuals should seek immediate medical attention if they experience new onset of (acute and persisting) chest pain, shortness of breath or arrhythmia (palpitations). Diagnosis is based on elevated troponin, C-reactive protein and electrocardiogram and/or MRI findings. Report all suspected cases to CARM as Medsafe continues to monitor this AEFI closely. Defer further doses of mRNA-CV if myocarditis or pericarditis occurs after vaccination. Seek specialist immunisation advice, on a case-by-case basis, to consider an appropriate alternative vaccination option, and timing for further doses (see section 5.6.2).

Anaphylaxis

Following approval for use in the US, the VAERS detected 47 cases of anaphylaxis after administration of just under ten million doses (around five cases per million doses) mRNA-CV (Pfizer/BioNTech). The median interval to symptom onset was ten minutes (range <1–1140 minutes), almost 90 percent occurred within 30 minutes of vaccination.[122] All were successfully treated with adrenaline. See section 5.6 for contraindications and precautions.

Frail elderly

A follow-up, after approximately two million doses of mRNA-CV were delivered through long-term residential care facilities to elderly and frail residents in the US found no increase in deaths post vaccination.[43] Deaths were to be expected and consistent with the all-cause mortality rate and causes of death for these individuals, who have multiple comorbidities, declining health and require end-of-life care.[43] There are no added safety concerns about the use of this vaccine in the elderly.[123]

History of Guillain-Barré Syndrome

There is no evidence of a higher rate of reporting of Guillain-Barré syndrome (GBS) following COVID-19 vaccination in individuals who have previously had GBS. Vaccination with mRNA-CV is preferred.

Adjuvanted recombinant COVID-19 vaccine – Nuvaxovid (Novavax)

Uncommon AEFI reported during clinical trials were lymphadenopathy, hypertension (observed in 1 percent of older adults for three days following vaccination), rash and injection site pruritus. One case of myocarditis was observed in a clinical trial occurring three days after second dose was deemed by the independent safety monitoring committee to most likely be viral myocarditis. No episodes of anaphylaxis were reported.[66] Three cases of myocarditis or myopericarditis and two cases of pericarditis were reported during two clinical trials (one case in placebo group) and in two cross-over studies. Although a causal relationship to the vaccine could not be confirmed, the European Medicines Agency listed heart inflammation as a potential risk.[112]

In a clinical trial, when rCV was given as a second dose after a first dose of mRNA-CV, similar systemic responses were observed to those given mRNA-CV as a second dose and local reactions were generally less frequent.[94]

A slightly increased incidence of local adverse events such as injection site tenderness and pain were reported during a clinical trial of rCV given concurrently with seasonal influenza vaccine (65 percent rCV plus influenza vs 53 percent for rCV alone of participants reported tenderness). This component of a randomised, placebo controlled clinical trial included 201 people who received rCV and QIV concurrently and 16 participants aged 65 years or older who received adjuvanted TIV.[64]

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