Accessible Published by De Gruyter September 8, 2021

Optimizing effectiveness of COVID-19 vaccination: will laboratory stewardship play a role?

Giuseppe Lippi ORCID logo, Brandon M. Henry and Mario Plebani ORCID logo

Coronavirus disease 2019 (COVID-19) is now regarded as one of the most tragic events to have occurred since the end of the World War II. With nearly five million deaths worldwide to-date and an epidemiological trend that is still imposing an enormous burden on healthcare, society and economy across the globe, widespread vaccination is paramount for mitigating the impact of severe acute respiratory infection coronavirus 2 (SARS-CoV-2) [1]. Without vaccination, the chance that the spread of this life-threatening infectious disease will wane is very low, almost null, and this perpetuates the need for continuous restrictive measures such as social distancing, banning mass gatherings, using face masks, performing repetitive diagnostic tests, and, last but not least, maintaining the risk of quarantine, lockdowns and closures, that will all contribute to further disrupt global economy and social life [2].

According to the World Health Organization (WHO), vaccination is regarded as simple, safe, and effective way to protect people against harmful diseases, especially before they are challenged with the pathogen. The colossal importance that vaccination has played in averting morbidity and mortality from infectious diseases was brilliantly highlighted in a comprehensive analysis published by Toor and colleagues [3], who concluded that vaccination against the 10 most common infectious diseases has saved over 50 million lives in the past two decades and will further permit to avert many more millions in the next 10 years.

In essence, all vaccines work by utilizing the natural defences of an organism for developing a sustained resistance to specific infections, ultimately strengthening the immune system, which responds to vaccination by (i) producing specific antibodies (i.e., humoral immunity), (ii) training immune cells to combat the pathogen, infected cells or to generate immune mediators for amplifying the immunological response (cellular immunity), as well as by (iii) triggering the generation of memory cells, which will especially help to face recurrent infections (Figure 1) [4]. In general, vaccine efficacy can be assessed by two means, that is evaluating clinical efficacy based on multiple domains and thus including medium- or long-term prospective and/or retrospective monitoring the number of patients with new or breakthrough infections, the viral load (in infected persons), the cases that require hospitalization, mechanical ventilation, intensive care unit admission, along with accurately recording the number of COVID-19-related deaths (Figure 1) [5, 6]. Assessing biological efficacy is another “surrogate” approach for predicting and verifying vaccine efficacy, which basically falls under the generic term of “immunogenicity”, and entails assessing – as previously mentioned – the production of neutralizing antibodies, the development of cell-mediated immunity or the persistence of an immunological memory. All these biological pathways work in synergy to protect a subject from being infected or re-infected, as well as to mitigate virus-induced local and systemic injuries, thus leading to a decreased risk of morbidity, disability and death when infected. Although such laboratory measures shall obviously be considered surrogate endpoints of vaccine effectiveness, their assessment provides a basic advantage, as it does not typically require a long prospective monitoring period, enables monitoring of real-world vaccine immunogenicity, and may provide “real-time” information to better tailor interventions for both single individuals and the population as a whole.

Figure 1: 
Contribution of laboratory medicine in optimizing the effectiveness of COVID-19 vaccination.
Abs, antibodies; COVID-19, coronavirus disease 2019; INF-γ, interferon gamma; RBD, receptor binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 1:

Contribution of laboratory medicine in optimizing the effectiveness of COVID-19 vaccination.

Abs, antibodies; COVID-19, coronavirus disease 2019; INF-γ, interferon gamma; RBD, receptor binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

SARS-CoV-2 serology is now universally considered a key aspect in assessing vaccine immunogenicity [7, 8]. Although a kaleidoscope of anti-SARS-CoV-2 immunoassays have been commercialized, several lines of evidence now suggest that measuring the serum levels of total or IgG class antibodies targeting SARS-CoV-2 spike protein or its receptor biding domain (RBD) are those that seem to better correlate with the endogenous virus neutralizing potential [9], [10], [11]. Recent evidence has been published that vaccine breakthrough, defined as detection of SARS-CoV-2 RNA (or antigen) ≥14 days after receipt of recommended doses of authorized COVID-19 vaccines, may depend on serum concentration of anti-SARS-CoV-2 antibodies. In a study carried out at a large medical center in Israel [12], where healthcare workers who received an mRNA COVID-19 vaccine were followed-up, the levels of anti-SARS-CoV-2 neutralizing antibody and anti-SARS-CoV-2 IgG were over 50% lower in infected subjects than in matched uninfected controls. Overall, a higher peri-infection value of anti-SARS-CoV-2 neutralizing antibodies was associated with a lower viral load, as reflected by higher cycle threshold values. Similar evidence has been reported in another investigation, where it was found that vaccine efficacy against primary symptomatic COVID-19 was directly related to the anti-SARS-CoV-2 level of anti-spike IgG, anti-RBD IgG and neutralizing antibodies achieved after receiving an adenovirus-based vaccine [13]. These findings converge to suggest that vaccine breakthrough, at least in terms of failure to prevent the development of an active viral infection and/or reinfection, may be strongly dependent on anti-SARS-CoV-2 antibodies, such that close (and possibly) repeated monitoring of subjects in whom immunogenicity would be expectedly lower may be highly advisable (Table 1). Importantly, monitoring anti-SARS-CoV-2 antibodies response may also be useful for deciphering the immunogenicity, and thus the possible differential effectiveness, of different COVID-19 vaccines. For example, Steensels reported that the Moderna mRNA-based vaccine elicited a significantly higher serological response compared to the similar Pfizer mRNA-based vaccine, and such increased response was more evident in baseline seronegative individuals and was consistent throughout different age ranges and sexes [14]. Similar evidence has been reported by Kaiser et al. in dialysis patients [15], thus reinforcing the concept that monitoring the immunogenicity of different COVID-19 vaccines by means of measuring anti-SARS-CoV-2 antibodies may be advisable for establishing a “vaccine stewardship”.

Table 1:

Updated list of major correlates of lower vaccine immunogenicity (reduced generation of anti-SARS-CoV-2 antibodies).

  1. (1)

    Older age (especially >65 years)

  2. (2)

    Sex (male)

  3. (3)

    Obesity, especially:

    1. (i)

      Central obesity

    2. (ii)

      Body mass index >25 km/m2

  4. (4)

    Cancer:

    1. (i)

      Hematological malignancies, especially

      1. Lymphoma

      2. Chronic lymphatic leukemia

      3. Multiple myeloma

    2. (ii)

      Specific treatments, especially:

      1. Cytotoxic chemotherapies

      2. Immune Checkpoint Inhibitors

      3. Tyrosine kinase inhibitors

  5. (5)

    Impaired renal function:

    1. (i)

      End-stage renal disease

    2. (ii)

      Hemodialysis

  6. (6)

    Cardiovascular disease, especially:

    1. (i)

      Hypertension

    2. (ii)

      Heart diseases

  7. (7)

    Immunosuppression

    1. (i)

      Conditions:

      1. Transplant recipients, especially:

        • (a) Thoracic organs

        • (b) Pancreas

        • (c) Kidney

        • (d) Liver

      2. Autoimmune and chronic inflammatory diseases, especially:

        1. (e)

          Inflammatory bowel disease

        2. (f)

          Rheumatoid arthritis

        3. (g)

          Systemic Lupus Erythematosus

        4. (h)

          Vasculitis

    2. (ii)

      Drugs, especially:

      1. Glucocorticoids

      2. Methotrexate

      3. Tacrolimus

      4. Mycophenolate

      5. Azathioprine

      6. Leflunomide

      7. CD 20 inhibitors (e.g., Rituximab)

      8. TNF inhibitors (e.g., Adalimumab, Infliximab)

      9. Abatacept, Belatacept

      10. B-cell depletion therapy

  8. (8)

    Infection with variants of concerns (especially those bearing “escape mutations”)

  9. (9)

    Variable immunogenicity of different types of COVID-19 vaccines

Another interesting aspect that should be considered is the possibility to routinely assess cellular immunity developing in COVID-19 vaccine recipients. For example, the QuantiFERON SARS-CoV-2 assay is an interferon-gamma release assay based on three different antigen tubes using a combination of proprietary antigen peptides specific to SARS-CoV-2, aimed to stimulate lymphocytes involved in cell-mediated immunity in heparinized whole blood. Briefly, the first of the three tubes contains CD4+ epitopes of the receptor binding domain comprised within the Spike protein S1 subunit, the second tube contains CD4+ and CD8+ epitopes from Spike protein S1 and S2 subunits, and the third tube contains CD4+ and CD8+ epitopes from S1 and S2, along with immunodominant CD8+ epitopes derived from whole viral genome [16]. These assays have already been reliably used for monitoring the cellular response in COVID-19 patients and for tailoring treatment [17], such that their usage for assessing and monitoring cellular immunity in recipients of COVID-19 vaccines seems indeed promising and warrants further scrutiny.

Last but not least, deciphering memory B cell response is another important aspect for predicting COVID-19 vaccines effectiveness. Recent data has shown that the kinetics of memory B cells producing anti-SARS-CoV-2 neutralizing antibodies may deserve special focus. Although sustained generation of these types of cells may not be fully effective at preventing vaccine breakthrough, it may be instead functional for reducing the likelihood of developing symptomatic or even severe illness, as a consequence of a timelier antibody response, especially when anti-SARS-CoV-2 circulating antibodies titer has remarkably declined. More specifically, the results of a recent investigation demonstrate that even if the serum anti-SARS-CoV-2 antibodies titer has consistently decreased nearly 7 month after administration of mRNA-based vaccines, the value of memory anti-spike protein and anti-receptor domain B cells remained consistently high, thus confirming that the immune system is somehow primed to face new SARS-CoV-2 infections, even with new strains, including some variants of concern [18].

In conclusion, Figure 1 attempts to summarize the important contribution that laboratory medicine may presently provide to enhance the real-world optimization of the effectiveness of COVID-19 vaccination. The assessment of these surrogate endpoints is essentially based on laboratory tests, and encompasses SARS-CoV-2 serological immunoassays, as surrogate measures of humoral immunity and neutralizing antibodies, interferon-gamma release assays, as surrogate tests aimed at deciphering and monitoring cellular immunity, along with flow cytometry techniques for assessing the presence and number of memory B cells. Notably, the value of monitoring anti-SARS-CoV-2 neutralizing antibodies is well documented in the literature. In a seminal article, Khoury et al. [19] underscored that the anti-SARS-CoV-2 neutralization level significantly predicts overall immune protection, thus providing a reliable basis for optimizing vaccine strategies aimed at controlling SARS-CoV-2 outbreaks. Conversely, major efforts are still needed to better standardize laboratory tests for investigating cellular immunity and evaluating their overall utility in clinical practice [20].

There is now an open debate on the distribution of COVID-19 vaccines among different settings and countries, with the need to set a delicate balance between administrations of the first vaccine dose to naïve individuals vs. the use of additional boosters for preventing waning of immunity in those who have already been vaccinated [21]. While this debate continues, we proffer that laboratory-guided vaccine stewardship may represent a feasible and potentially valuable tool in the ongoing and strenuous fight against COVID-19.


Corresponding author: Prof. Giuseppe Lippi, Department of Neuroscience, Biomedicine and Movement, Section of Clinical Biochemistry, University Hospital of Verona, Piazzale L.A. Scuro, 10 37134, Verona, Italy, Phone: 0039 045 8122970, Fax: 0039 045 8124308, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

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Published Online: 2021-09-08
Published in Print: 2021-11-25

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