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Inicio Vacunas (English Edition) Autumn 2023 SARS-CoV-2 immunization: Who should be vaccinated and how?
Journal Information
Vol. 24. Issue 4.
Pages 261-265 (October - December 2023)
Vol. 24. Issue 4.
Pages 261-265 (October - December 2023)
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Autumn 2023 SARS-CoV-2 immunization: Who should be vaccinated and how?
Vacunación frente al SARS-CoV-2 en otoño de 2023: ¿a quién y cómo hay que vacunar?
Fernando Moraga-Llopa,b,
Corresponding author

Corresponding author.
, Magda Campins-Martíc
a Societat Catalana de Pediatria, Barcelona, Spain
b Asociación Española de Vacunología, Barcelona, Spain
c Facultad de Medicina, Universidad Autónoma de Barcelona, Barcelona, Spain
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Although it is no longer a public health emergency of international concern, the COVID-19 pandemic is not yet over and we must continue epidemiological surveillance and vaccination, based on the current status of the infection. The emergency was declared by the World Health Organisation (WHO) on 30 January 2020, and ended on 5 May 2023, after 3 years and 3 months.1 In Spain, the end of the health crisis caused by COVID-19 was declared on 4 July 2023 (BOE of 5 July 2023).

SARS-CoV-2 has remained endemic among us, but does not, for the moment, show a seasonal pattern of spread similar to that of influenza. In Spain, the months with the highest mortality due to COVID-19 after the first wave of the onset of the pandemic in 2020, were January and February 2021 and January and July 2022.2–4 Therefore, seasonal behaviour is not defined and the circulation of new, much more transmissible variants, such as omicron and its subvariants, holiday movements, and the relaxation of non-pharmacological protective measures are factors to be taken into account.

The decreasing trend in the number of deaths, hospitalisations and admissions to intensive care units (ICU), and the high levels of population immunity, especially vaccine and hybrid immunity, were the determining factors in the WHO's declaration of the end of the health emergency. Nevertheless, COVID-19 remains a health and social problem, and the risks and uncertainties about its evolution are still a threat to global health. The WHO declaration is accompanied by temporary recommendations for all member states, including the integration of vaccination against COVID-19 into the lifelong vaccination programme, especially in high-risk individuals.1,5

It is estimated that 14 billion doses of vaccine administered worldwide have prevented more than 20 million deaths from COVID-19.6 However, the virus continues to circulate and will continue to cause ICU admissions and deaths, and millions of patients will continue to live with the sequelae of persistent long COVID-19. In Spain, life expectancy has been reduced by 1.5 years, and across the WHO European region 36 million people may have developed clinical symptoms of long COVID-19 during the first 3 years of the pandemic.7

In Spain, hospitalisations due to COVID-19 during 2020 and 2021 were 498 789, 10.9% in ICUs, and the case fatality rate was 14.3% in admitted patients (71 437 people).8 In 2022, although confirmed COVID-19 mortality was 20% lower than in 2021, it represented for the third consecutive year the leading cause of death, with 31 559 deaths, corresponding to 6.8% of the total, followed by ischaemic heart disease, with 28 687 deaths, and in third place by cerebrovascular disease, with 24 558 deaths.2–4

In this new post-emergency phase, vaccination, together with non-pharmacological measures, remains the most effective preventive measure as outlined in the WHO statement1 and needs to be integrated into the life-long immunization programme. Efforts should be maintained to increase vaccination coverage in individuals in high-risk groups with the recommended vaccines and to continue to actively address uptake and demand issues with communities. To this end, a document has been published in Spain, Recommendations for vaccination against influenza and COVID-19 in the 2023–2024 season in Spain, approved by the Public Health Commission on 12 July 2023.9

Who should be vaccinated?

Given the current epidemiological situation, the vaccination strategy in autumn 2023 should include, first and foremost, the groups at greatest risk by age, i.e. people aged 60 years and older. Mortality from COVID-19 in Spain in 2022 was concentrated in the elderly: 95.9% were aged 60 years and older (70.8% aged 80 years and older).2–4 In the period 2020–2021, hospitalisations in those aged 64 years and older (267 110 cases) accounted for 53.5% of all admissions and 44.9% of those requiring ICU admission; furthermore, case fatality was highest in patients admitted to ICUs aged 74 years and older (27.1% in 2020 and 31% in 2021).8

In second place are people from the age of 6 months with some type of immunocompromise, including severe immunosuppression and inborn immunity impairment, and also those suffering from chronic diseases, especially those affecting the vascular endothelium, such as diabetes and cardiovascular diseases, with a list of more than 20 risk conditions, according to the document approved by the Public Health Commission.9

Thirdly, the vaccination strategy should cover people living and working in nursing homes, homes for the disabled and the chronically ill and institutionalised; pregnant women in any trimester of pregnancy; health and social care staff; and all contacts of patients belonging to at-risk groups.9

Furthermore, vaccination should be available to all persons who request it, even if they do not belong to the groups in which vaccination is recommended, provided that at least 5 months have elapsed since a previous dose of vaccine was administered or infection has occurred.

Which vaccines should be administered?

In September 2022, the European Medicines Agency (EMA) approved the first adapted or modified vaccines, which are part of the second-generation group of vaccines and are messenger RNA vaccines: Comirnaty Original/Omicron BA.1 (Pfizer/BioNTech), Comirnaty Original/Omicron BA.4–5 (Pfizer/BioNTech), Spikevax bivalent Original/Omicron BA.1 (Moderna), and Spikexax bivalent/Omicron BA.4–5 (Moderna). A new group of vaccines, recombinant protein vaccines, has also been added: Nuvaxovid (Novavax), VidPrevtiyn Beta (Sanofi/GSK), and Bimervax (HIPRA).10

These second-generation vaccines have shown additional protection, compared to vaccines made with the original strain, against hospitalisation, severe forms of the disease and death from COVID-19 caused by omicron subvariants.11

Worldwide, since the beginning of 2023, more than 90% of SARS-CoV-2 infections have been caused by XBB-descendant sub-lineages (data as of 29 July 2023, GISAID).12 Omicron XBB is the sublineage with the highest immune escape to date; relative to Omicron BA.5, the subvariants XBB.1.5 and XBB.1.16 have 20 and 23 mutations, respectively, which justifies updating the composition of the vaccines.13,14

The need for new preparations responds to the decreasing effectiveness of available vaccines due to the progressive loss of immunity over time (waning immunity), due to the emergence of variants with increased vaccine escape, i.e. evading neutralising antibodies, especially against infection and mild disease.15,16 The administration of a booster dose of adapted BA.4–5 vaccines increases the neutralising antibody titre and cellular immunity against XBB, but with much lower titres than those achieved against the previous subvariants.13 The safety and reactogenicity profiles of the booster doses are similar to those of primovaccination.

In May and June 2023, recommendations for new vaccines for the coming autumn were communicated by various agencies.

On 8 May, the International Coalition of Medicines Regulatory Authorities (ICMRA)17 discussed the future of SARS-CoV-2 vaccination and especially the composition of vaccines for the coming autumn. The representative of the US Food and Drug Administration (FDA) reported that the spike protein of XBB.1.5 is similar to that of XBB.1.16 (only a difference of 2 mutations in the receptor binding domain [RBD] and in the N-terminal domain of the protein [NTD]) and to that of XBB.1.9. For their part, the EMA representative at ICMRA stated that the evidence presented supports the value of having monovalent vaccines tailored to the circulating variants, and that pending further data, they should contain XBB, although not all approved platforms in the EU will be available by next autumn.

The WHO Technical Advisory Group (TAG-CO-VAC), in a report dated 18 May,18 also issued recommendations on the composition of future vaccines. Noting that current vaccines remain highly protective against severe disease and death, and that protection against symptomatic disease is limited and less durable, it recommends upgrading to XBB.1 lineages, such as XBB.1.5 or XBB.1.16 in monovalent formulation. These vaccines may be administered as primary or booster vaccination. This recommendation is based on the following considerations: (a) the ancestral virus and its closest derivatives are no longer circulating, (b) the vaccine antigens of the ancestral virus induce undetectable or very low titres of antibodies against currently circulating SARS-CoV-2 variants, and (c) the inclusion in bivalent vaccines of the ancestral virus reduces the immune response to the new antigens compared to monovalent vaccines (a phenomenon known as immune imprinting or “original antigenic sin”). This explains the progressive decline in the effectiveness of current bivalent vaccines as new variants of SARS-CoV-2 emerge.

The EMA and the European Centre for Disease Prevention and Control (ECDC) have published a joint statement, dated 6 June 2023, on the update of adapted COVID-19 vaccines and considerations for use in autumn this year.19,20 A monovalent XBB.1.5 vaccine is recommended to provide protection against current dominant and emerging strains, or other formulations that achieve an immune response against this subvariant. The following simplified vaccination schedule is proposed, although the recommendations of national health authorities should always be followed: (a) persons over 5 years of age, 1 dose of the matched monovalent vaccine, (b) children under 5 years of age with no history of vaccination or previous SARS-CoV-2 infection, a primary series consisting of 2 or 3 doses, depending on the matched monovalent vaccine administered (as with first generation vaccines),21 and (c) persons with immunosuppression, administer additional doses according to national recommendations. For revaccinations, a minimum interval of 3–4 months since the last dose or since the onset of infection should be expected.

The FDA's Vaccines Related Biological Products Advisory Committee (VRBPAC) at its meeting on 15 June 2023,22,23 selected the omicron subvariant XBB.1.5 (whose structural characteristics are quite similar to those of others currently circulating, such as XBB.1.16 and XBB.2.3) as a unique vaccine candidate for use in the autumn of this year. The following is a summary of the data on the investigational vaccines presented at this meeting by Moderna, Pfizer, and Novavax. The other 2 recombinant protein vaccines available in Spain (Sanofi/GSK and HIPRA) will not present any adapted vaccine for the 2023–2024 season and will remain the originals.

Monovalent messenger RNA vaccine XBB.1.5 adapted from Moderna (Spikevax, designation of the original)

Immunogenicity studies conducted to test the neutralising capacity of antibodies generated by a booster dose of bivalent Original (Wuhan)/Omicron BA.4–5 vaccine in individuals with or without previous infection showed very low titres against XBB.1.5 (geometric mean neutralising antibody titres [GMT] of 556 and 298, respectively). Preclinical studies with monovalent matched XBB.1.5 vaccine used as primary series show very high induction of neutralising antibody titres (GMT of 16 672 versus XBB.1.5 and 20 915 versus XBB.1.16). A Phase 2/3 immunogenicity and safety clinical trial of the monovalent XBB.1.5 vaccine (third booster) in adults aged 18 years and older who had received 4 doses of mRNA vaccine showed a greater than 16-fold increase in neutralising antibody titre over the pre-booster value against XBB.1.5 and a 10-fold increase against XBB.1.16 (GMT of 2579 and 2263, respectively). The safety profile was similar to that observed with already licenced vaccines).24

Monovalent messenger RNA vaccine XBB.1.5 adapted from Pfizer (Comirnaty, designation of original)

Based on data from clinical trials with the bivalent Original (Wuhan)/Omicron BA.4–5 and the monovalent Original vaccine administered as a fourth dose in persons with or without previous infection, the neutralising antibody titres induced by both vaccines against the Omicron subvariants XBB.1.5 and XBB.1.16 were lower (GMT of 111 and 93, respectively) than those against BA.4–5 (GMT between 1076 and 1197). In contrast, results from preclinical studies show that a booster dose with the adapted monovalent vaccine XBB.1.5 induces a high neutralising response against the sub-lines XBB.1.5, XBB.1.16, and XBB.2.3 (GMT of 1800, 3766, and 3020, respectively). Similar results have been obtained with this vaccine used as a primary vaccination. The safety profile was also similar to that observed with already licenced vaccines.25

Monovalent XBB.1.5 adjuvanted recombinant protein vaccine adapted from Novavax (Nuvaxovid, designation of original)

Preclinical studies in mice primovaccinated with 2 doses of monovalent XBB.1.5 vaccine show high titres of neutralising antibodies to the XBB.1.5 and XBB.1.16 subvariants (GMT of 4554 and 4156, respectively). Studies in mice primed with bivalent vaccine (Original/Omicron BA.5) and given a dose of monovalent XBB.1.5 showed similar results (GMT of 5816 and 8413, respectively). Concordant data have been observed in preclinical studies in macaques. Induction of cell-mediated immune responses against the XBB26 variant has also been demonstrated.26

HIPRA vaccine

The current vaccine is bivalent, with a Beta-Alpha dimer, and adjuvanted (Bimervax).27 An adapted form, a monovalent dimer of an omicron XBB subvariant, is under development and the clinical trial is scheduled to start in November 2023 (source: HIPRA). Based on preliminary data from 2 sub-cohorts of individuals participating in the initial Bimervax clinical trial (1 receiving 3 prior doses of Comirnaty mRNA vaccine and the other 2 doses of Comirnaty mRNA and 1 dose of Bimervax), administration of a fourth dose induced neutralising antibody titres to XBB.1.5 at 14 days (GMT between 257 and 307, respectively).28

Sanofi/GSK vaccine

The current vaccine (VidPrevtiyn Beta) will not be available in an adapted form for the time being. There is some preliminary immunogenicity data for this vaccine against XBB, but it is not published (source: Sanofi).


Recommendations regarding which persons should be vaccinated with which vaccines will have to be modified according to the epidemiological evolution of the pandemic (emergence of new variants, according to transmissibility, and degree of vaccine escape) and the availability of new vaccines (mucosal, broad-spectrum, or other). In addition, epidemiological surveillance and monitoring of vaccine safety and effectiveness, as well as vaccination coverage, should continue. COVID-19, for the moment, is not a seasonal disease like influenza, as SARS-CoV-2 is behaving very differently and time will tell.

On the same day as this article was being finalised, a WHO communiqué was published, dated 9 August 2023, indicating that several variants of interest (VOIs) are currently being analysed, including EG.5 (also called Eris), an omicron variant lineage descended from XBB.1.9.2 and XBB.1.5, with a subvariant EG.5.1 accounting for 88% of the sequences available for EG.5. This new variant is already present in more than 50 countries, its incidence is increasing and has led to an increase in the number of infections. Its most relevant characteristics are greater transmissibility and more immune escape than XBB, although it does not seem to be associated with greater severity.29

Therefore, as we have already pointed out several times, epidemiological surveillance (diagnostic tests, case reporting, and virus sequencing) must continue and the WHO Director-General has reminded us that “the risk remains that a more dangerous variant could emerge that could cause a sudden increase in cases and deaths”.



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Please cite this article as: Moraga-Llop F, Campins-Martí M. Vacunación frente al SARS-CoV-2 en otoño de 2023: ¿a quién y cómo hay que vacunar? Vacunas. 2023. https://doi.org/10.1016/j.vacun.2023.08.001

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