key: cord-1031485-jibxd9ua
authors: Barriere, J.; Carles, M.; Audigier-Valette, C.; Re, D.; Zoubir, A.; Seitz-Polski, B.; Gounant, V.; Descamps, D.; Zalcman, G.
title: Third dose of anti-SARS-CoV-2 vaccine for patients with cancer: Should humoral responses be monitored? A position paper
date: 2021-12-16
journal: Eur J Cancer
DOI: 10.1016/j.ejca.2021.12.011
sha: 0ddded4069ff4cf3ee46d55cddaa1be24d1ffd58
doc_id: 1031485
cord_uid: jibxd9ua

Taking into account higher risk of severe coronavirus disease 2019 (COVID-19) or death among patients with cancer, as well as impaired immunogenicity following anti-SARS-CoV-2 vaccines, in addition to waning immunity, booster dosing appears mandatory in this patient population. This review sought to provide reasonable evidence so as to assist oncologists in their daily practice, helping them decide when an anti-SARS-Cov2 antibodies (Abs) dosage should be scheduled following a full two-dose vaccination and if necessary, propose an early third dose (D3). Such D3 could apply to non-responder patients with anti-Spike (S) Abs titers < 40 binding antibody units (BAU)/mL. For low-responder patients with anti-S Abs titers between 40 BAU/mL and 100/260 BAU/mL (suggested area of uncertainty), an early D3 may similarly be proposed. Nevertheless, this D3 could be administered in a less urgent manner, taking into account associated co-morbidities and regional epidemic incidence rates. This latter strategy may comprise a monthly dosage of anti-S titers so as to better assess the kinetics of waning immunity. For responder patients with anti-S titers above 260 BAU/mL, we suggest to follow the recommendations outlined for the general population. Given this context, patients with anti-S titers above 1000 BAU/mL should be given the possibility to undergo anti-S titer control after 3 months, designed to assess rapid humoral waning immunity. We strongly recommend that patients with cancer be included into observational serological monitoring studies or clinical trials that are dedicated to severe immunocompromised patients without any humoral seroconversion after D3.

Several countries around the world are in the process of setting up their anti-SARS-CoV-2 vaccination booster campaign, predominantly designed for people attaining the 6-month time interval following the second vaccine shot. This strategy is supported by several studies focused on the durability of vaccine-induced antibodies (Abs) levels and clinical studies conducted in the general population, as well (1) (2) (3) (4) (5) . Nevertheless, to date, there are no recommendations allowing for a personalized prescription dedicated to immunocompromised people, including patients with cancer displaying lower anti-SARS-CoV-2 vaccine immune responses (6-10).

Another issue is still unresolved, and it concerns the exact timing of the earlier waning immunity observed at post-vaccination in immunocompromised patients, such as patients with cancer undergoing immunosuppressive therapy. Besides, the proposal for an international standard of SARS-Cov2 immunoglobulins (11) implies establishing a reliable equivalence among different commercially available kits, which is not yet possible (12) . Thus, defining an antibody threshold that is associated with ineffective immunity is still tricky. In addition to this, immunity cannot be exclusively summarized by the humoral response (13) . Therefore, further clinical studies are required to precisely define the optimal vaccination schedule in such specific patient populations. Prior to providing recommendations concerning the third dose (D3) and serum Abs titer thresholds for daily oncology practice, a thorough review of the existing scientific evidence is mandatory.

We have summarized herein the available data concerning the efficacy of anti-SARS-CoV-2 vaccines administered to patients with cancer with either solid tumors or hematological malignancies (HM) in preventing severe infection, hospitalization, and death. This has been carried out specifically in relation with patients' post-vaccine humoral responses. Such review sought to provide reasonable evidence to help oncologists in their daily practice, enabling them to decide: 7 Based on selected serological studies, comparative median anti-S Abs titers, converted in BAU/mL, among the different populations of interest with cancer have been schematized in (35) using Abbott IgG II. This illustration clearly depicts the substantial differences in post-vaccination median anti-S titers measured in patients with cancer, varying from 230 (Roche Elecsys) to 671 (Abbott IgG II) BAU/mL, being four to ten times lower than those observed in healthy controls. Nevertheless, these anti-S Abs titers were at least 14 times higher than the values documented in patients with HM, whereas patients treated using anti-CD20 Abs exhibited a complete lack of seroconversion, with median anti-S titers at 0 BAU/mL after D2.

Concerning clinical vaccine efficacy in patients with cancer, Heudel et al. reported convincing data involving 1503 vaccinated cancer patients (36). These authors reported a statistically significant difference in mortality between patients who received two vaccine doses in comparison with those who received only one dose. This latter observation clearly suggests that delaying the D2 from 4 to 12 weeks after D1 injections, as proposed in early 2021 in some countries due to vaccine shortage, could be deleterious to patients with cancer, thereby increasing the risk of SARS-CoV-2 breakthrough infection between D1 and D2 injection timing.

With this background in mind, we were able to observe that some patients were probably not sufficiently protected based on a traditional 2-dose vaccination schedule. As of April 2021, the French authorities rendered it thus possible to administer a D3 to immunocompromised patients, thereby targeting at first transplanted patients and those suffering from MH (37). By end June 2021, the first global publication focusing on D3 was published, primarily involving transplanted patients (38). This was quickly followed by other series confirming the beneficial contribution of D3 in these immunocompromised patients (39-40). In a randomized trial (41), either D3 or placebo was randomly administered to transplanted patients, using mRNA-1273 vaccine (Moderna) at Month 2 following D2 injection. At Month 4, overall 55% of patients having received D3 exhibited anti-S glycoprotein-specific IgG receptor-binding domain (RBD)

Abs levels of at least 100 arbitrary units (AU)/mL (Roche Elecsys) versus 18% in the placebo group (P <0.001). Nevertheless, on account of the small patient number and the short followup, no conclusion with respect to the associated clinical protection could be drawn. In this trial, J o u r n a l P r e -p r o o f only one single patient from the placebo group actually developed COVID-19, exhibiting a preinfection anti-RBD Abs level of 75 AU/mL.

In the oncology field, three studies with currently available data evaluated the impact of early D3 vaccine injection in poor humoral responders' patients with LM (42), with thoracic cancer (35) and in allogenic transplanted patients in remission of a HM (43). Nevertheless, these studies employed different serological assays rendering data comparison rather difficult, unless using the conversion factors proposed by the World Health Organization (WHO) (NIBSC code 20/136). These factors enable conversion of AU used by each manufacturer into binding antibody units (BAU) (44). In this context, a factor x 0.972 (≈ 1) for Roche Elecsys SARS-CoV-2 anti-S Abs (Roche Elecsys), x 0.142 for Abbott SARS-CoV-2 IgG II Quant-test (Abbott IgG II), or x 2.6 for DiaSorin Liaison SARS-CoV-2 TrimericS IgG (DiaSorin TriS IgG) must be applied in order to convert the assay results for obtaining comparative data (12) .

In the first study, Re et al., while using Roche Elecsys assay, demonstrated that LM patients with positive anti-S Abs titers after D2 similarly exhibited increased neutralizing antibodies (Nabs), with a > 80% correlation between Nabs levels and anti-S Abs titers above > 400 BAU/mL (42). In patients with multiple myeloma, the median anti-S Abs titer prior to D3 was 100 BAU/mL, rising to 2700 BAU/mL (p <0.0001) thereafter, which is comparable to anti-S Abs serum levels from vaccinated healthy donors 6 to 8 weeks after D2 (7), using the same technique. However, some patients with CLL or non-Hodgkin lymphoma, as well as those undergoing anti-CD20 therapy, displayed no seroconversion after either D2 or D3, whereas a significant stimulation of T-cell response was observed in a subset of patients. Around 20% of patients were considered "double negative," thereby exhibiting neither B nor T-cell responses.

Indeed, these patients were considered to be vaccine failures.

In 42 allogenic transplanted patients, three BNT162b2 mRNA vaccine doses were similarly shown to result in a significant rise of anti-SARS-CoV-2 Abs, with IgG (S-RBD) (Abbott IgG II) levels increasing from 737 AU/mL (105 BAU/mL) to 11 099 AU/mL (1576 BAU/mL) (p <0·001) (43). In the latter study, two factors were associated with the rise of Abs to the protective Ab threshold. These factors included a B-cell count exceeding 0·25 g/L in the peripheral blood at D3 and an IgG (S-RBD) concentration exceeding 1000 AU/mL after D2, namely patients with more than 140 BAU/mL after conversion. In this study, 52% of patients displayed anti-S Abs levels below 4160 AU/mL (590 BAU/mL); the latter levels are considered a surrogate measure of vaccine protection, corresponding to a 0·95 probability of obtaining in-vitro evidenced NAbs, which were, however, not correlated to a clinical infection.

Vaccine research is primarily aimed to identify a vaccine-induced humoral response that predicts protection from infection or disease (45). Immunization after viral infection and vaccine efficacy have previously been related to NAbs rates (46), thereby reducing clinical events (47) or, in specific conditions, helping consider revaccination (i.e., booster dose, challenge dose, or revaccination with a complete series) (48) .

Currently, evidence is accumulating establishing a definite link between the level of SARS-CoV-2 humoral immunity and COVID-19 clinical protection, without any threshold level being clearly relevant for clinical practice (49) (50) (51) (52) . While delayed anti-SARS-CoV-2 NAbs production was associated with increased rates of COVID-19 death (53), poor anti-S responders after vaccination in the oncology setting were clearly likely to keep the poorest prognosis (23).

Immunization against SARS-Cov-2 appears durable in the case of remaining Nabs after 12 months from infection (54) (55) . Half-life of anti-S (RBD) IgG levels from 393 convalescent COVID-19 health care workers (HCW) was found to be 725 days (24 months) (55), with an incidence of SARS-CoV-2 infections of 0.4 per 100 person-years compared to 12.22 in COVID-19-negative HCW. This observation is highly suggestive of a durable protection against reinfection after a first COVID-19 infection. Indeed, PCR-proven reinfections were rare in the young and international population of Qatar (56) . Natural infection most likely elicits strong protection against reinfection, displaying an efficacy of approximately 95% for at least seven months. Whether such long protection induced by natural infection could be similar to that acquired following vaccination is highly questionable. A non-negligible reinfection rate among populations vaccinated for more than 6 months was already observed (4) (5) . These reinfections were associated with higher infectious power and viral burden, with immune host J o u r n a l P r e -p r o o f defenses being overwhelmed in the presence of low anti-S Abs levels, as recorded with B.1.617.2 Delta variant of concern (VOC) (57). In a large population study involving patients RT-PCR-tested for SARS-CoV-2 following two doses of mRNA BNT162b2 vaccine, there was a significantly increased infection risk observed in individuals who received their last vaccine dose more than 146 days prior, particularly among patients aged over 60 years (4) . In this cohort, patients with solid tumor were identified as one of the subgroups exhibiting higher risk for such post-vaccine waning immunity (odds ratio = 0.642 [0.494-0.834]).

The best immunity stimuli against SARS-CoV-2 are most likely the association of a previous COVID-19 infection followed at least 2 months after natural infection by a single mRNA vaccine dose, when anti-S Abs levels in such patients are compared with those measured following two mRNA vaccine in injections in SARS-CoV-2-naive subjects in the general population (58) (59) (60) or patients with cancer (61) . In addition, although the protective Abs levels appear to be higher in the days following vaccination versus following a COVID-19 infection, the decrease is likely more rapid in the vaccinated group, with antibody titers decreased by up to 40% at each subsequent month, whereas in convalescents, these antibody titers were shown to decrease by less than 5% per month (62) . Six months after BNT162b2 vaccination, 16.1% subjects displayed Abs levels below the seropositivity threshold of < 50 AU/mL (Abbott IgG II), whereas only 10.8% of convalescent patients were below the < 50 AU/mL threshold 9 months after SARS-CoV-2 infection.

These recent data suggest the need for a D3 booster dose among defined populations. However, to date, no randomized trial data are available, enabling physicians to choose between a strategy based on a potential serological threshold or a vaccination schedule designed for all, without prior biological examination. This strategy has currently been selected by various states that since summer 2021, have started revaccination in the population considered at risk, recently reporting clinical benefits in terms of reinfection rates (1).

Several published studies reported correlations between anti-S Abs and NAbs levels and SARS-CoV-2 (re)infection incidences in either cancer patients or the general population. 

The lack of technique and assay harmonization, which often impedes cross-comparison of studies, renders it difficult to establish a clear definition of serum anti-S titer cutoff. Such a cutoff threshold could serve to provide strong guidance in terms of vaccination booster timing.

Otherwise, while waiting, only a vaccination schedule for all that is not based on individual serological rates should be recommended.

As mentioned above, the international standard for anti-SARS-CoV-2 immunoglobulins (NIBSC code 20/136), which was proposed by the WHO, was designed to uniformize dosage results, by defining common units, meaning the binding antibody units per milliliter (BAU/mL) (44). Ab titers were determined after SARS COV-2 infection, and four groups were described:

high responders with median anti-S IgG titers of 832 BAU/mL, mid responders with median anti-S IgG titers of 241 BAU/mL, as well as low S IgG / high nucleocapsid (N) antigen responders with 86 median anti-S IgG titers of BAU/mL and low responders with median anti-S IgG titers of 53 BAU/mL. As already stated, all manufacturers are supposed to give concertizer factor for their assay that allow to uniformize results (11) . In August 2020, the FDA authorized the emergency use of COVID-19 convalescent plasma for treating hospitalized patients affected by COVID-19. Later, in March 2021, the FDA provided a Table of Tests Acceptable for Use in the Manufacture defining a High Titer COVID-19 Convalescent Plasma.

For Roche Elecsys, the required level of anti-S Abs was ≥132 AU/mL (≈BAU/mL), for Abbott IgG II on Architect or Alinity, this level was ≥840 AU/mL (120 BAU/mL), whereas for DiaSorin TriS IgG, it was ≥52 AU/mL (135 BAU/mL) (66).

Roche Elecsys, measure total anti-S Abs, including IgG, IgA, and IgM. In addition, the assay targets differ in recognizing either the entire spike protein, S1 and S2 subunits cleaved from the spike, or the receptor-binding domain (RBD) of the spike protein from the spike S1 subunit. In J o u r n a l P r e -p r o o f all assays, the manufacturer is thought to provide detection range, clinical specificity, and sensitivity.

Despite WHO's proposal, clinical follow-up studies investigating immune responses over time following either infection or vaccination, often employ various commercial tests for IgG assays, and this with or without conversion to BAU/mL (67) (68) (69) (70) (71) . Such studies are not always able to establish reliable cutoffs, which could be applied to clarify which SARS-Cov-2 Abs levels would support re-vaccination of former infected or vaccinated people, owing to waning immunity. A surprising issue is that even though the sensitivity and specificity of various tests are excellent (72) (76) . The comparability of quantitative SARS-CoV-2 Abs tests was highly dependent on the timing of blood collection after vaccination. Though 3 weeks after D1, anti-S Abs titers (converted in BAU/mL) provided by Abbott IgG II were three times higher than those measured using Roche Elecsys, 11 weeks after D1 injection, the values obtained when using Roche Elecsys were twice as high as those attained by Abbott IgG II, and 3 weeks after D2, these

Roche Elecsys values were even 5 to 6 times higher than those of Abbott IgG II. According to the authors, standardization of blood collection timing is required for the comparability of different quantitative SARS-COV-2 Abs assays.

However, for low anti-S Abs titers (poor-responders), the impact of the difference appears less crucial. Therefore, defining a low anti-S Abs level remains relevant. Even when using conversion factors, head-to-head comparison remains hazardous. Comparison data with clinically relevant cutoffs depending on the assays used are currently urgently required.

Since most Western countries are likely to proceed to a booster dose vaccine for their whole population over 60 or 65 years old, the current issue is to provide clear guidance for younger people, especially if they suffer from cancer. To be able to compare future data across different studies, assays, and countries, our first recommendation is to publish the results pertaining to J o u r n a l P r e -p r o o f anti-S Abs serology using the WHO BAU/mL units. Indeed, though the techniques may not be completely comparable, this will at least avoid potential sources of confusion when analyzing comparative data. Moreover, comparative studies using different immunological assays must be performed, with results compared at different time point. Ideally, international units should then be proposed (11) .

Despite remaining uncertainties, in our view, the currently available data are sufficient to propose serological monitoring in patients at risk of lower seroconversion rates, including patients with cancer. Moreover, our data similarly support serology reimbursement by Health authorities with dosing proposed 3-4 weeks after D2, and during follow-up, as necessary.

Indeed, as already mentioned, the delay in the appearance of Nabs is now a well-established risk factor for COVID-related death (53) . In addition, a low level of post-vaccination antibodies has been formally identified as a risk factor of death (36). Moreover, in the general population, waning immunity has been established to occur from the fifth month post-vaccination, with initial higher anti-S IgG titers.

Anti-S Abs dosage at 3-4 weeks after D2 would seek to assess the responders and identify three different groups (Fig. 1) , depending on their anti-S IgG levels.

We have summarized our approach in Fig. 2 .

We strongly recommend proposing an early D3 to no-responder patients with cancer (red zone: anti-S Abs titer < 40 BAU/mL (< 280-300 AU/mL for Abbott IgG II assay) ( Fig. 1-2 ). The second category defines as low-responder patients with cancer (yellow zone: anti-S Abs titer between 40 and 100-260 BAU/mL, suggested area of uncertainty, i.e., values between 280-300 and 700-1800 UA with Abbott IgG II assay, [ Fig. 1-2] ). These patients may also be proposed a D3. Yet, this third injection could be carried out in a less urgent manner, while taking into account associated co-morbidities and regional epidemic incidence rates, followed by a monthly dosage of anti-S Abs titers so as to assess the kinetics of waning immunity, if possible. These patients, likely to be less at risk than those of the first group, could markedly benefit from an early D3. Once again, while such a strategy seems to be worth it, more data are still needed to best identify potential predictive rates of increased responses to a booster. Like the no-responder group, administration of monoclonal Abs should be considered (see above).

The last category can be defined as responders (green zone: anti-S Abs titer > 260 BAU/mL[ > 1800 AU/mL for Abbott IgG II] Fig. 1-2 ). This group may wait a few months before receiving D3, following the recommendations established for the general population. Taking into account the slope of waning immunity with time in patients with comorbidities, including patients with cancer (4), we suggest considering anti-S Abs dosage at 3 months, particularly in intermediateresponders, meaning those with anti-S Abs titers between 100 BAU/mL and ~1000 BAU/mL. Given this context, D3 vaccine should be administered as soon as anti-S Abs levels decrease, becoming close to or below 100-260 BAU/mL, as seen in Situation #2.

As advantage of such policy, this would enable us to spare vaccine doses and keep them for developing countries or higher-risk patients, including solid organ transplant patients, octogenarians, etc. In addition, delaying D3 would have the additional advantage of further expending the protection period of these patients by moving forward the limit of humoral protection. After 6 months from vaccination, depending on the recommendations in force according to the patient's age, a D3 may be offered without serological control unless the patient is part of a serological monitoring observatory.

After administering D3, regardless of the indication and threshold selected for such decision, we suggest to measure anti-S Abs levels at 3-4 weeks following D3, to ascertain the rise of protecting serum Abs above 260 BAU/ml. If it is the case, a new measurement could be performed at 5-6 months. Yet, we do not know what will be the slope of the anti-S Abs decrease, which may indeed be slower than the one following the two initial shots. Whether ulterior J o u r n a l P r e -p r o o f injections would be needed is still unknown, owing to uncertainties about the viral circulation level at that time across the five continents. Other uncertainties pertain to the VOCs that will be predominantly circulating during the first 2022 semester, and the eventual future vaccine mRNA formulations that will later be at our disposal. Clearly, there are currently no scientific data in relation to an eventual fourth vaccine dose injection (D4) after eventual immunity waning following D3. However, one exception deserves to be mentioned here. Indeed, such repeated vaccine injections have already been administered to some severely immune compromised patients, to those with solid organ transplantation, or to HM patients treated using anti-CD20 therapeutic monoclonal Abs. Nevertheless, such repeated vaccine dose injection has not been proven efficient to date.

We strongly recommend the continuation of observational studies, with the pooling of their data, in order to obtain solid epidemiological data. A prospective study (77) is currently in progress, which should enable us to establish with certainty a link between the antibody level and clinical protection over time, with a specific focus on patients with cancer with cancer.

We are aware that our recommendations based on anti-S Abs titers could be extensively debated, until prospective large-sized study data are being made available, enabling us to validate our proposals. Moreover, even if waning specific T immunity has similarly been reported, specifically depending on age and being directed against VOC (78) , it is clear that humoral immunity does not summarize the whole anti-SARS-CoV-2 immunity field (13;79).

The same is true for the oncology domain (80) . The presence of memory T-and B-cells has been clearly shown in germinal centers (81) , which could support higher protection towards SARS-CoV-2 in vaccines, even in the event of low serum anti-S IgG titers. The contrast between high breakthrough infection levels in large populations vaccinated during the December 2020 -January 2021 period, and the relatively low level of severe or deadly COVID-19 overwhelming hospitals, notably in Israel or Singapore, would suggest the existence of such memory immunity, thereby protecting people against severe COVID-19, even in the event of serum anti-S IgG decreases. However, we are still lacking routine, fast, and cost-effective techniques to monitor specific T-response or specific memory immune cell responses, which would allow us to ascertain such hypothesis. Therefore, pragmatically, we feel that serum anti-S IgG monitoring could offer a relatively low-cost monitoring strategy, whereas is still an J o u r n a l P r e -p r o o f imperfect readout for assessing anti-SARS-CoV-2 immunity in high-risk cancer patients. We urgently call for reimbursement of such tests for patients with cancer, along with a prospective evaluation of our proposed strategy. Given the risk of vaccine failure in some patients with cancer, we strongly encourage vaccination campaigns with a full-dose schedule for households, with a 6-months booster following countries policies, close contacts and the general population. 

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