To our knowledge, this is the first report of cancer patients on active treatment for solid malignancies, which provides not only immediate data about seroconversion after the complete primary course of vaccination with mRNA-based SARS-CoV-2 vaccines but also extended data three months after. Compared to healthy controls, cancer patients on anticancer treatment achieved adequate seroconversion rates after completing the primary course of vaccination regardless of the type of anticancer therapy received. However, anti-SARS-CoV-2 S1 IgG antibody production was built more gradually than in healthy controls, which was especially prominent after the first vaccination dose. However, anti-SARS-CoV-2 S1 IgG production was moderate in patients receiving ICI compared to patients receiving chemotherapy or targeted therapy. Similarly, after three months following vaccination, there was a decline in anti-SARS-CoV-2 S1 IgG levels of patients receiving chemotherapy and ICI, but not targeted therapy, compared to healthy controls.
Since COVID-19 pandemics have had devastating consequences in the frail population of cancer patients, it is vital to gather as much reliable data as to demonstrate whether vaccination benefit this population.2–7, 9 Due to the paucity of data available, patients are often reluctant to be vaccinated since the efficacy and safety profile of vaccines in this population is unknown, leaving them at low vaccination levels – from 40–60%. 19–21
From reports available so far, it is evident that patients with hematological malignancies do poorly in terms of seroconversion rates compared to patients treated for solid tumors. That is both due to the impaired immune system caused by the disease itself and due to highly immune-suppressive therapy. 15,22−25
Similar to our study, others also showed more gradual anti-SARS-CoV-2 S1 IgG antibody build-up after the first vaccination.15,22,26 A French group clearly showed that both vaccination doses are necessary to achieve adequate protection, since only 55% of cancer patients developed specific anti-SARS-CoV-2 antibodies after a single dose, compared to 100% of healthy individuals. Also, levels of anti-SARS-CoV-2 antibodies are lower in cancer patients compared to healthy individuals and irrespective of the timing of anticancer therapy received. 26,27 This is further confirmed in our group of patients, where the seroconversion rate after the first dose was significantly lower than after the second (64% versus 96%; P < 0.0001). In the largest prospective trial reported so far, cancer patients performed exceptionally well in terms of seroconversion after vaccination. Moreover, they defined a threshold of anti-SARS-CoV-2 S1 IgG levels based on their neutralizing capacity, that categorized patients to adequate and suboptimal responders – the latter probably needing the third vaccine dose to achieve sufficient SARS-CoV-2 S1 IgG levels to offer reliable protection against severe disease.28 A recent systematic review and meta-analysis provided data on promising antibody response after COVID-19 vaccination in cancer patients with seroconversion rates > 90%. 29
We have shown that patients receiving ICI have the lowest anti-SARS-CoV-2 antibody production, especially after the first dose of vaccine. After vaccination with two doses, antibody levels seem to be comparable regardless of anticancer therapy received. Similarly, an Israeli group provides data on 102 solid cancer patients being vaccinated and the lowest anti-SARS-CoV-2 IgG titres achieved in patients receiving chemo-immunotherapy or immunotherapy plus targeted therapy. 30 This data is further supported by the Greek group that found significantly lower antibody production after only one dose of vaccine in patients receiving ICI. 31 Since ICI are showing an immunomodulatory mode of action in patients infected with SARS-CoV-2, thus reducing cytotoxic effects and cytokine release, there could also be a potential effect on delaying anti-SARS-CoV-2 S1 IgG antibody production after vaccination. 32
The present study shows that antibody levels against SARS-CoV-2 are high for most cancer patients on active anticancer treatment after vaccination with both doses, offering enough protection to escape a severe disease development. This is further supported by the fact that out of our cohort of 112 patients, only three were infected with COVID-19 and symptomatic after a complete vaccination course. Most of the patients were adequate responders after vaccination with both doses and were considered to have a high probability of protection against severe COVID-19 infection, having anti-SARS-CoV-2 S1 IgG Ab above 880 ng/ml (44 BAU/ml).
Nevertheless, there was a marked decline in anti-SARS-CoV-2 S1 IgG following three months after vaccination with both doses, especially in the group of patients receiving chemotherapy or ICI. That further supports the idea of a third vaccination dose in this patient population, which is also safe and feasible as shown by recent publications. 33
In our study, there were no new safety concerns raised in terms of reactogenicity or adverse events (AE) following vaccination. Other reports also show less frequent emergence of AE after vaccination in cancer patients than healthy subjects as seen in the trials.10,11,15,28,34 Much fewer local or systemic AEs are reported, especially after the second vaccination, with 70% of cancer patients reporting no AE whatsoever.15,28 Similar to our results, a large US study showed 70% of patients experiencing local and up to 50% of patients systemic AEs after either vaccination. 34 It should be noted that cancer patients are already affected by their disease, symptom,s and possible adverse effects of anticancer treatment, thus leaving them less perceivable for possible vaccination AEs.
Since anti-SARS-CoV-2 S1 IgG assay has high sensitivity and specificity, it is easily reproducible, quick, and non-costly, and correlates well with immunogenicity achieved after infection, it is thought reasonable to expect that a high level of anti-SARS-CoV-2 S1 IgG antibodies after vaccination correlates well with the protection against worse disease outcome as shown in the early phases of vaccine development. 35,36 However, antibody levels only represent humoral immunity, whereas cellular immunity protecting from severe courses may be preserved despite lower antibody levels in cancer patients compared to controls. The upper limit of antibody measurements was at 2020 ng/ml, so the differences between different groups in our cohort could be even greater than observed here. Another shortcoming might be the underrepresentation of certain groups of patients or malignancies, mirroring the frequency of certain patient groups being treated at certain centers. The strength of our study is a centralized laboratory for analysis of antibody levels, which reduces the chances of differences in methodology and execution of assay. In addition, the study was prospectively planned with every time point for blood sampling being pre-arranged, thus reducing the inconsistency in study execution. Also, only patients with solid cancers were included, which further harmonizes the group being investigated and pronounces potential other variables that play a role in the antibody production.