Longitudinal Study of SARS-CoV-2 Vaccinations and Infections in Patients with Gastrointestinal Cancer: Stabilizing Immune Responses and Neutralizing Emerging Variants with Variant-Adapted Antigen Exposures

Abstract

This longitudinal study examined how active gastrointestinal (GI) cancer types affect immune responses to SARS-CoV-2, focusing on the ability to neutralize the Omicron variants. Patients with GI cancer (n = 168) were categorized into those with hepatocellular carcinoma, hepatic metastatic GI cancer, non-hepatic metastatic GI cancer, and two control groups of patients with and without underlying liver diseases. Humoral and cellular immune responses were evaluated before and after Omicron antigen exposures. In the pre-Omicron era, humoral SARS-CoV-2 immunity decreased after three antigen contacts without further antigen exposure. While Omicron neutralization was significantly lower than wildtype neutralization (p < 0.01), Omicron infections were yet mild to moderate. Additional Omicron exposures improved IgG levels (p < 0.01) and Omicron neutralization (p < 0.01). However, this effect was significantly less intense in patients with active GI cancer, particularly in patients with pancreaticobiliary neoplasms (PBN; p = 0.04), with underlying immunodeficiency (p = 0.05), and/or under conventional chemotherapy (p = 0.05). Pre-Omicron SARS-CoV-2 immunity prevented severe clinical courses of infections with Omicron variants in patients with GI cancer. However, in patients with PBN, with underlying immunodeficiency, and/or under conventional chemotherapy initial contacts with Omicron antigens triggered only reduced immune responses. Thus, subgroups could be identified for whom booster vaccinations are of special clinical significance.

Keywords: SARS-CoV-2; booster antigen contacts; gastrointestinal cancer; hepatocellular cancer; immune responses; metastases; omicron neutralization; waning immunity.

Figure 1

Humoral immune responses to pre-Omicron and Omicron SARS-CoV-2 antigen exposures. Balanced levels of SARS-CoV-2 anti-spike IgG (a) in all patients in the pre-Omicron era. Moreover, the capacities to neutralize the wildtype (b) as well as the Omicron variants (c) of SARS-CoV-2 were comparable in all patients. However, neutralization of the wildtype was significantly higher than that of the Omicron variants (d). Following Omicron antigen exposures, both levels of SARS-CoV-2 anti-spike IgG (a) as well as the capacity to neutralize the Omicron variants (c) increased significantly. Abbreviations: C1: control 1 (patients in follow-up care without underlying liver disease); C2: control 2 (patients in follow-up care with underlying liver disease); G1: group 1 (patients with hepatocellular carcinoma); G2: group 2 (patients with hepatic metastic gastrointestinal cancer); G3: group 3 (patients with non-hepatic metastic gastrointestinal cancer); IgG: immunoglobulin G; sNABs: surrogate neutralization anti-bodies.

Figure 2

Impact of the type of cancer on humoral immune responses to pre-Omicron and Omicron SARS-CoV-2 antigen exposures. Balanced levels of SARS-CoV-2 anti-spike IgG (a) in all patients in the pre-Omicron era. Moreover, the capacity to neutralize the wildtype and/or the Omicron variants were comparable (b,c). Following Omicron antigen exposures, both levels of SARS-CoV-2 anti-spike IgG (a) as well as the capacity to neutralize the Omicron variants (c) increased significantly in all patients except for those with pancreaticobiliary cancer. “Other” included duodenal carcinoma, gastrointestinal stroma tumors, and cancer of unknown primary with most likely GI origin. Abbreviations: CRC: colorectal cancer; GEJC: gastroesophageal junction cancer HCC: hepatocellular carcinoma; IgG immunoglobulin; NET: neuroendocrine tumors; PBN: pancreaticobiliary neoplasms; sNABs: surrogate neutralization antibodies.

Figure 3

Multivariable analyses on factors potentially influencing immune responses to SARS-CoV-2 antigen exposures. (a) Effects on levels of SARS-CoV-2 anti-spike IgG. (b) Effects on the capacity to neutralize the wildtype of SARS-CoV-2. (c) Effects on the capacity to neutralize the Omicron variants of SARS-CoV-2. Any active cancerous disease under oncological treatment was associated with significantly lower SARS-CoV-2 anti-spike IgG levels (p = 0.04; (a)) and a lower capacity to neutralize the Omicron variants (p = 0.03; (c)). The ability to neutralize either the wildtype or the Omicron variants of SARS-CoV-2 was significantly impaired in patients with underlying relevant immunodeficiency (p = 0.01; (b) and p = 0.05; (c)). Considering different tumor types, it was confirmed that the capacity to neutralize the Omicron variant was significantly impaired in patients with PBN (p = 0.04).

Figure 4

Study design. From the beginning of the second calendar week in 2022, Omicron was the predominant variant of SARS-CoV-2 in Germany, though the infection rate was initially very low in our cohort. Omicron-adapted vaccines became available in October 2022, and the number of Omicron infections significantly increased in our cohort at the same time. Based on this knowledge, we defined a pre-Omicron and an Omicron era. In three previous studies, we evaluated short-term effects of the basic immunization (4, 12, and 24 weeks after two wildtype-based vaccinations against SARS-CoV-2; first blue box), followed by analyses on the effects of a first wildtype-based booster vaccination (4, 12, and 24 weeks after a third wildtype-based booster vaccination; second blue box), as described elsewhere [19,20,21]. In the present analysis, we focused on the ability to neutralize the Omicron variants of SARS-CoV-2 (orange box). Thereby, we firstly investigated longer-term effects of pre-Omicron antigen booster contacts considering both wildtype-based vaccinations and/or infections with pre-Omicron variants. The patients of our cohort had a mean of 3.45 (2–5) pre-Omicron antigen contacts at this point of time. A second analysis focused on short-term effects of a first Omicron antigen booster contact by Omicron-adapted vaccination or infection with an Omicron variant (four to eight weeks after this Omicron contact). Abbreviations: IgG: immunglobulin G; IGRA: Interferon-Gamma Releasing Assay; sNABs: surrogate neutralizing antibodies.