Le Infezioni in Medicina, n. 1, 1-5, 2023

doi: 10.53854/liim-3101-1


The future for COVID-19 vaccines: public health assessment and perspectives based on scientific evidence

Massimo Andreoni1, Paolo Bonanni2, Andrea Cossarizza3,4, Giovanni Gabutti5, Francesco Gesualdo6, Andrea Grignolio7,8, Giancarlo Icardi9, Pierluigi Lopalco10, Francesco Vitale11

1Infectious Diseases Unit, University of Tor Vergata, Rome, Italy;

2Department of Health Sciences, University of Florence, Florence, Italy;

3Istituto Nazionale per le Ricerche Cardiovascolari, Bologna, Italy;

4Department of Medical and Surgical Sciences for Children and Adults, Univ. of Modena and Reggio Emilia School of Medicine, Modena, Italy;

5Gruppo di Lavoro “Vaccini e Politiche Vaccinali” della Società Italiana di Igiene, Medicina Preventiva e Sanità Pubblica (SItI), Rome, Italy;

6Unità di Medicina Predittiva e Preventiva, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy;

7Facoltà di Medicina e Chirurgia, Università Vita-Salute S. Raffaele, Milan, Italy;

8Centro Interdipartimentale per l’Etica e l’Integrità nella Ricerca, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy;

9Dipartimento di Scienze della Salute, Università degli Studi di Genova, Genova, Italy;

10Dipartimento di Scienze e Tecnologie Biomediche e Ambientali, Università del Salento, Lecce, Italy;.

11Dipartimento di Promozione della Salute Materno-Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro”, Università degli Studi di Palermo, Palermo, Italy

Article received 21 January 2023, accepted 13 February 2023

Corresponding author

Francesco Gesualdo

E-mail: f.gesualdo@gmail.com


The development and use of messenger RNA-based (mRNA) vaccines against the SARS-CoV-2 spike protein have proven to be highly effective against symptomatic COVID-19, especially for severe forms. Since the declaration of a public health emergency in early 2020, however, the SARS-CoV-2 virus has continuously evolved, giving rise to several variants that have caused and continue to cause concern in the scientific community. Currently, viruses circulating worldwide belong to the Omicron lineage, with several identified sub-variants. In response to virus mutation, mRNA vaccines have been adapted into bivalent vaccines containing two mRNAs: one encoding the original Wuhan SARS-CoV-2 spike protein and one encoding the BA.1 or BA.4-5 spike protein of the Omicron sub-variant. This strategy is based on the hypothesis that the immune system’s response improves when variants are included in the vaccine, leading to an increase in the magnitude and diversity of both the humoral and cellular immune response. The evidence gathered to date confirms the use of bivalent vaccines as the optimal strategy.

In the light of current knowledge, and in the awareness of the impossibility of making precise predictions on the evolution of the COVID-19 pandemic, as a group of experts we propose some considerations for the progressive evolution of vaccination against SARS-CoV-2 from pandemic to endemic vaccination.

Keywords: Covid-19, vaccines, public health.


The pandemic caused by SARS-CoV-2 is evolving in a new epidemiological scenario. The emergence of new variants as an attempt by the virus to escape human immunity developed through both vaccines and natural infections, goes along with a trend to acquire a more stable genetic and antigenic form, that, however, SARS-CoV-2 has not yet reached.

Indeed, in many regions of the world, the circulation of the virus is stably high, due to inadequate control measures. Therefore, SARS-CoV-2 evolution remains uncertain, and the genetic and antigenic characteristics of future variants cannot be predicted [1].

Recently, new strains of SARS-CoV-2 have raised concern among scientists, as one or more of the identified Omicron sub-variants could cause new COVID-19 epidemic waves during autumn and winter seasons, and even during warmer seasons, like the wave that was recorded in July 2022 [2].

The most effective tool to finally overcome the health emergency is the vaccine. A joint effort is still needed to modulate the vaccination strategy through vaccination campaigns, active calls targeting fragile categories, and the involvement of all professionals that work close to patients, such as general practitioners, pediatricians, specialist doctors and pharmacists.

Vaccine protection against mild SARS-CoV-2 infections is guaranteed mainly by the presence of neutralizing antibodies (nABs). Differently from severe SARS-CoV-2 infections, immunogenic protection towards mild cases depends on the match between the virus strain contained in the vaccine and the circulating variant [3].

On the other hand, protection against severe infection is essentially generated by the T-lymphocyte response and by the reactivation of the immunological memory, providing cross-protection also against antigenically-distinct variants. This type of protection is therefore only to a minor extent influenced by a mismatch between the vaccine variant and the circulating variant.

Furthermore, the duration of T cell protection is apparently higher than that provided by antibodies, due to both the generation of long living memory cells and the capacity of virus-specific T lymphocytes to exert different functions at the same moment [4, 5].

After the primary vaccination with the ancestral strain, or even a booster of an adapted vaccine, high protection against mild infections caused by the newly circulating variants cannot therefore be expected. However, data showing protection against severe infections, regardless of the variant, is now established.

Despite the need to develop vaccines specifically targeting the Omicron variant, it is important to point out that the original mRNA vaccines partially retained the ability to prevent asymptomatic or pauci-symptomatic infections [6]. Consequently, the original vaccine still had an impact on Omicron’s high transmission and infection capacity, even if this variant has several mutations of the spike receptor-binding domain.

It needs to be emphasized that the primary goal of vaccination against COVID-19 is to reduce hospitalizations, severe illness and deaths due to SARS-CoV-2, thus reducing the impact on population health and on the healthcare system.

The present paper reports a short literature review and a set of considerations with regards to the future of SARS-CoV-2 vaccination, by a group of Italian experts in infectious diseases, vaccinology, immunology, public health and communication. The literature review was conducted on Pubmed and was based on high quality secondary publications (systematic reviews and meta-analysis) focusing on the monovalent mRNA vaccine against SARS-CoV-2, and on the high-quality scientific papers evaluating the bivalent mRNA vaccine against SARS-CoV-2 published up to December 2022. The group of experts participated in a structured discussion on the published literature and on the role of the bivalent vaccine against SARS-CoV-2 in the Italian scenario, during an in-person meeting held in Rome in October 2022, and carried on the subsequent discussion and the preparation of the manuscript from remote.


In the absence of a correlation to protection, and considering the fast-changing epidemiology of the virus, the best indicator of the benefit achievable with vaccines is the measurement of vaccination effectiveness (VE). VE indicates the efficacy of the vaccine used in a real-life setting and can be measured with different epidemiological study designs by comparing the frequency of cases and/or of different outcomes in vaccinated individuals to unvaccinated population.

The administration of the original virus (Wuhan) vaccine as a booster dose has been shown to confer high levels of protection against severe disease outcomes for all variants, including Omicron:

Although effectiveness data confirm the importance of booster dose administration even with the original vaccine, several variants of SARS-CoV-2, the Variants of Concern (VoC), showing increased transmissibility and immune escaping, have emerged since the beginning of the pandemic [11, 12].

Omicron and its sub-variants are the most antigenically divergent from the original variant. These, as possible future variants, or emerging sub-variants, may cause significant morbidity and mortality even in vaccinated and/or previously infected subjects [1].

These observations led to the development of bivalent mRNA vaccines as an optimal approach to induce a more potent, long-lasting, and broad immune response against SARS-CoV-2. The bivalent booster dose strategy is based on the hypothesis that the immune system’s response improves when more than one variant is present in the vaccine. This characteristic leads to an increase in the magnitude and diversity of both the humoral and cellular immune response [13].

In addition to the mRNA sequence coding for the Omicron strain spike (BA.1 or BA.4/5), the presently available bivalent mRNA vaccines keep in the formulation the mRNA sequence coding for the Wuhan strain spike protein and add the mRNA sequence coding for the Omicron strain spike (BA.1 or BA.4/5). Recent data demonstrate the advantages of the bivalent mRNA vaccine strategy:

From an immunological point of view, there are two lines of defense, an immediate one consisting of antibodies, and a more long-lasting one consisting of immunocompetent cells. Seasonal bivalent vaccine might boost humoral immunity and broader the cross-protection against both circulating and new strains that could potentially appear in the future.


Conflicts of interest

MA received research grants and personal fees for collaborations, for preparing educational material, and for lectures from Gilead Sciences, Janssen-Cilag Tibotec, Viiv Healthcare, Merck Sharp and Dohme, Abbvie, Angelini, Menarini, Pfizer, Moderna and Astra Zeneca.

PB received grants for epidemiological and HTA research from different vaccine companies (GSK, MSD, Sanofi Pasteur, Pfizer, Seqirus, Astra Zeneca) and fees for taking part to advisory boards or educational events on different vaccines from the same companies and from Janssen and Moderna.

AC received research grants and personal fees for collaborations, for preparing educational material, and for lectures from ViiV Healthcare, Menarini Biomarkers Singapore, Moderna, Beckman Coulter, Thermofisher, Sony Biotech, Miftek and Bio-Rad.

GG received personal fees for advisory board membership and consultancy from Emergent BioSolutions, the GSK group of companies, MSD, Merck, Pfizer, Sanofi Pasteur Italy, Moderna and Seqirus, as well as personal fees for lectures from MSD, Pfizer, and Seqirus.

FG received support for participating in MSD and Moderna meetings.

AG has been a member of advisory boards and was invited speaker at regional, national and international congresses for MSD, Novartis, Moderna.

GI received funding for scientific advisory boards, travel, and speaker honoraria from Pfizer, GSK, MSD, Sanofi Pasteur and Seqirus.

PL has been a member of advisory boards and was invited speaker at regional, national and international congresses for GSK, MSD, Moderna, Pfizer, Sanofi, Seqirus.

FV has been a member of advisory boards; has obtained grants for epidemiological studies and was invited speaker at regional, national and international congresses for GSK, Pfizer, MSD, Sanofi, Seqirus, Moderna, Janssen, AstraZeneca.


None to declare.


[1] Interim statement on the composition of current COVID-19 vaccines. https://www.who.int/news/item/17-06-2022-interim-statement-on--the-composition-of-current-COVID-19-vaccines. Accessed 19 Dec 2020.

[2] Big COVID-19 waves may be coming, new Omicron strains suggest. https://www.science.org/content/article/big-covid-19-waves-may-be-coming-new-omicron-strains-suggest. Accessed 19 Dec 2020.

[3] Munro APS, Feng S, Janani L, et al. Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial. Lancet Infect Dis. 2022; 22 (8), 1131-1141.

[4] Sette A, Sidney J, Crotty S. T Cell Responses to SARS-CoV-2. Annu Rev Immunol. 2022. Epub ahead of print. doi: 10.1146/annurev-immunol-101721-061120.

[5] De Biasi S, Paolini A, Lo Tartaro D, Gibellini L, Cossarizza A. Analysis of Antigen-Specific T and B Cells for monitoring immune protection against SARS-CoV-2. Curr Protoc. 2023; 3 (1), e636.

[6] McLean G, Kamil J, Lee B, et al. The impact of evolving SARS-CoV-2 mutations and variants on COVID-19 vaccines. mBio. 2022; 13 (2), e0297921.

[7] He X, Su J, Ma Y, Zhang W, Tang S. A comprehensive analysis of the efficacy and effectiveness of COVID-19 vaccines. Front Immunol. 2022; 13, 945930.

[8] McConeghy KW, White EM, Blackman C, et al. Effectiveness of a second COVID-19 vaccine booster dose against infection, hospitalization, or death among nursing home residents - 19 States, March 29-July 25, 2022. MMWR Morb Mortal Wkly Rep. 2022; 71 (39), 1235-1238.

[9] Tenforde MW, Patel MM, Gaglani M, et al. Effectiveness of a third dose of pfizer-biontech and moderna vaccines in preventing COVID-19 hospitalization among immunocompetent and immunocompromised adults - United States, August-December 2021. MMWR Morb Mortal Wkly Rep. 2022; 71 (4), 118-124.

[10] Report esteso ISS covid-19: sorveglianza, impatto delle infezioni ed efficacia vaccinale Aggiornamento nazionale 9/11/2022 - ore 12:00. https://www.epicentro.iss.it/coronavirus/bollettino/Bollettino-sorveglianza-integrata-COVID-19_9-novembre-2022.pdf. Accessed 19 Dec 2020.

[11] Ahmad A, Fawaz MAM, Arafeen Aisha A. A comparative overview of SARS-CoV-2 and its variants of concern. Infez Med. 2022; 3, 328-343. Doi: 10.53854/liim-3003-2

[12] Farahat RA, Abdelaal A, Umar TP, et al. The emergence of SARS-CoV-2 Omicron subvariants: current situation and future trends. Infez Med. 2022; 4, 480-494. Doi: 10.53854/liim-3004-2

[13] Chalkias S, Eder F, Essink B, et al. Safety, immunogenicity and antibody persistence of a bivalent Beta-containing booster vaccine against COVID-19: a phase 2/3 trial. Nat Med. 2022; 28 (11), 2388-2397.

[14] Chalkias S, Harper C, Vrbicky K, et al. A Bivalent Omicron-Containing Booster Vaccine against COVID-19. N Engl J Med. 2022; 387 (14), 1279-1291.

[15] Scheaffer SM, Lee D, Whitener B, et al. Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice. Nat Med. 2022 Oct 20.

[16] Alsoussi WB, Malladi SK, Zhou JQ, Liu Z, Ying B, Kim W, et al. SARS-CoV-2 Omicron boosting induces de novo B cell response in humans. bioRxiv [Preprint]. 2022 Sep 22:2022.09.22.509040.