key: cord-0903468-u06t81pw
authors: Jena, Anuraag; James, Deepak; Singh, Anupam K.; Dutta, Usha; Sebastian, Shaji; Sharma, Vishal
title: Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients with IBD: A Systematic Review and Meta-Analysis
date: 2022-02-19
journal: Clin Gastroenterol Hepatol
DOI: 10.1016/j.cgh.2022.02.030
sha: d5a74a854b1d2c396122689c656ca6080240aea2
doc_id: 903468
cord_uid: u06t81pw

Background The serological responses after SARS-CoV-2 vaccination may be attenuated in immunocompromised individuals. Aims To systematically evaluate the seroconversion rates after complete COVID-19 vaccination in patients with inflammatory bowel disease (IBD). Methods Electronic databases were searched to identify studies reporting response to COVID-19 vaccination in IBD. Pooled seroconversion rates after complete vaccination were calculated. Subgroup analysis for vaccine types was also performed. Pooled seroconversion rates for various drugs/classes were also estimated. The pooled rates of breakthrough infections in vaccinated IBD patients were estimated. The pooled neutralization rates after complete vaccination were also estimated. The studies reporting durability of titers were systematically assessed. Results A total of 46 studies were included. The pooled seroconversion rate for complete vaccination (31 studies, 9447 patients) was 0.96 (95%CI, 0.94-0.97, I2=90%). When compared to healthy controls, the pooled relative risk of seroconversion was lower (0.98; 0.98-0.99, I2=39%). The pooled seroconversion rates were statistically similar among various drug classes. The pooled positivity of neutralization assays (8 studies, 771 participants) was 0.80 (95%CI, 0.70-0.87, I2=82%). The pooled relative risk of breakthrough infections in vaccinated IBD patients was similar to vaccinated controls (0.60, 95%CI, 0.25-1.42, I2=79%). Most studies suggested that titers fall after 4 weeks of COVID-19 vaccination and the decay was higher in patients on anti-TNF alone or combination with immunomodulators. An additional dose of COVID-19 vaccine elicited serological response in most non-responders to complete vaccination. Conclusion Complete COVID-19 vaccination is associated with seroconversion in most patients with IBD. The decay in titers over time necessitates consideration of additional doses in these patients.

Vaccination against SARS-CoV-2 has been the main strategy for the control of COVID-19 pandemic across the globe. A number of vaccines have been approved in different countries. The mechanisms of action of various vaccines differ substantially but the major approved vaccines [mRNA, AAV (adeno-associated virus) and inactivated] have demonstrated good immune responses and protection from severe disease in clinical trials. 1 However, the clinical trials typically exclude patients with immune mediated inflammatory diseases (IMIDs) including inflammatory bowel disease (IBD). 2 IBD is a state of altered immune function-partly due to the underlying disease and partly to the immune modifying therapies. A subset of patients with IBD may have worse outcomes in SARS-CoV-2 infection. Vaccination is an important strategy to reduce infections and adverse outcomes due to COVID-19. 3 Previous data have shown that the seroconversion rates in patients with solid organ transplants and malignancies are suboptimal raising concerns about the efficacy of COVID-19 vaccines in immunocompromised individuals. 4, 5 Previous systematic review in patients with IMIDs suggest that certain subsets (especially those on B cell depleting therapies) may be at a risk of inadequate serological response to COVID-19 vaccination. This systematic review had limitations including the fact that it included multiple IMIDs with varying patients and drug therapies. 2 Responses to certain traditional vaccines including influenza and Hepatitis B may be attenuated in patients with IBD especially those on systemic immunosuppression. 6, 7 In addition to possibly reduced seroconversion rates with COVID-19 vaccination in IBD, there are concerns about the potential accelerated rate of decay in antibody titers with certain therapies. This may potentially reduce efficacy of the vaccine over time, especially in wake of emergence of newer variants of concern (VOC). 8 A number of studies which report on seroconversion after COVID-19 vaccination in IBD have been published. However, these studies have different populations (type of IBD, drugs treatment) and differing vaccination schedules (single or two doses, type of vaccine i.e mRNA or AAV). Therefore, we performed a systematic review regarding the efficacy and seroconversion rates with the use of COVID-19 vaccination in IBD to help inform clinical practice in patients with IBD. We also systematically assessed the durability of the antibody responses with time. Further, we assessed the evolving data on responses to an additional dose of COVID-19 vaccination after complete initial series. complete vaccination. We also extracted the corresponding seroconversion rates for healthy controls. For studies which reported the breakthrough infections after complete vaccination in IBD patients, we also extracted data if corresponding data in vaccinated controls was provided. We extracted data regarding seroconversion rates after complete vaccination in respect to the current IBD therapies. The positivity rates of neutralization assays were also extracted when available. The T cell response rates were also extracted and qualitatively summarized. The studies reporting measurement of antibody titers at multiple time periods were assessed to look for durability or any decay in the antibody titers. For each of the eligible studies we also included details regarding the publication (authors, and geographic location of study, specific cohort, type of publication), underlying IBD (numbers, age, gender, ulcerative colitis or Crohn's disease) and current drug treatment.

We estimated the pooled seroconversion rates (positivity of anti-spike or anti-receptor binding domain antibodies as defined in individual studies) after COVID-19 vaccination in IBD. We calculated seroconversion rates after incomplete or complete vaccination depending on the type of vaccine. The pooled relative risk for seroconversion in IBD patients as compared to healthy controls calculated. The overall pooled seroconversion rates were also calculated for each of the drug types separately by pooling data from relevant studies. We made a pooled estimate only if at least three studies with a minimum of five participants reported the seroconversion rates for a particular therapy. The pooled breakthrough infection rates in completely vaccinated IBD patients was calculated and pooled relative risk in comparison to vaccinated controls was also determined. We also calculated the pooled positivity of neutralization assays in patients with IBD and relative risk of neutralization positivity as compared to the control population. The presence of neutralizing antibodies was as per the definitions used in individual studies.

We used the R statistical software version 4.0.1 for the analysis and used the meta and metafor packages in addition to the base package. 11 We used the random effects model with inverse variance approach to report the pooled seroconversion rates and Mantel and Haenszel method for the pooled relative risk. Logit transformations were made for the individual seroconversion rate before computing pooled summary. I 2 and P values were used for the assessment of heterogeneity. We planned to address any significant heterogeneity (>50%) using subgroup analysis for the vaccine type. We also planned to use the Baujat plot to identify studies contributing to heterogeneity and if a biologically plausible reason could explain the heterogeneity and guide a subgroup analysis.

Two investigators made independent assessments of methodological rigor and risk of bias in the included studies using the relevant Joanna Briggs Institute (JBI) Critical appraisal checklist. JBI tool for prevalence studies was used to assess the studies which described the response to vaccines without any control group or any comparison with a non-vaccinated cohort. 12 This includes assessment of appropriateness of the included population, and the sampling, description of subjects and if vaccine response was assessed appropriately and similarly in all individuals. The appraisal tool for cohort studies was used in studies where control groups were present and the tool included questions about similarities in groups and assessment of exposure (vaccine) and outcomes (response to vaccine). 13 Publication bias was assessed using Funnel plot and Egger test. 14 J o u r n a l P r e -p r o o f

Of the 617 records identified after database search, 128 were duplicates. Of the 489 titles which underwent initial screening, 449 were removed for various reasons and 40 articles underwent full text screening. Additional 27 articles were identified from conference abstracts. Eventually, 46 articles were included in the meta-analysis. Full PRISMA flow chart of study selection is depicted in Figure 1 . Table 1 shows the details of the 46 included studies with the study type, type of population and the information provided. Supplementary Table 3 shows the excluded studies with reasons of exclusion.

For the seroconversion after complete vaccination (Supplementary Table 2 ) of COVID-19 vaccination there were 31 eligible studies (9447 participants) reporting the serological response. The pooled seroconversion rate was 0.96 (95%CI, 0.94-0.97, I 2 =90%) (Figure 2 ). When the subgroup analysis was done for the vaccine subtype, there were 22 studies (5485 participants) reporting about efficacy of m-RNA vaccine. The pooled seroconversion rate after complete m-RNA vaccination was 0.97 (95%CI, 0.96-0.98, I 2 =77%). The pooled seroconversion rate after complete AAV vaccine (7 studies-2192 participants) was lower (0.87, 95%CI, 0.78-0.93, I 2 =89%) ( Figure 2) . The pooled seroconversion rates after complete vaccination with Pfizer, Moderna, JNJ (Ad26.COV2.S) and Astra-Zeneca were 0.96 (0.93-0.98, I 2 =77%), 0.98 (0.97-0.99, I 2 = 0), 0.78 (0.65-0.88, I 2 =23%) and 0.90 (0.72-0.97, I 2 =86%) (Supplementary Figure 1) . When compared to the healthy controls, the pooled relative risk (12 studies, 830 controls and 1469 IBD patients) of seroconversion in patients with IBD after complete COVID vaccination was lower (0.98; 95% CI-0.98-0.99, I 2 =39%) but was similar for mRNA vaccine on subgroup analysis (0.99, 95%CI, 0.97-1.00, I 2 = 50%). (Supplementary Figure 2) . The definitions of seroconversion and the assays used in individual studies were variable and are shown in Supplementary Table 4 .

For incomplete vaccination, there were 8 studies (2030 participants) which reported seroconversion after incomplete COVID-19 vaccination in patients with IBD. The pooled seroconversion rate was 0.76 (95%CI, 0.57-0.88, I 2 =98%) (Supplementary Figure 3) . The pooled relative risk of seroconversion after incomplete COVID vaccination was lower in the IBD patients as compared to healthy controls (0.94; 95%CI, 0.89--0.99, I 2 =55%) (Supplementary Figure 4 ).

Overall, there were eight studies (771 participants) which reported the positivity of neutralization assays after complete COVID vaccination. The pooled positivity rates were 0.80 (95%CI, 0.70-0.87, I 2 =82%) (Supplementary Figure 5) . When compared to healthy controls, the positivity of neutralization assays post complete vaccination were lower in the IBD group (Pooled RR-0.85, 95%CI, 0.75-0.96, I 2 =77%) (Supplementary Figure 6) . The definitions of positivity of neutralization assays with the duration at which they were measured as reported in individual studies are shown in Supplementary Table 5 Seroconversion in patients stratified by therapies

The pooled response rate after complete COVID-19 vaccination in IBD patients who were not on any treatment was 0.98 (95%CI, 0.95-0.99, I 2 =0%). The pooled seroconversion rate with the use of steroids was 0.93 (95%CI, 0.75-0.99, I 2 =38%). The pooled seroconversion rate after complete vaccination in patients on 5-aminosalicylates was 0.98 (95%CI, 0.96-0.99, I 2 =0). The pooled seroconversion rates in patients on immunomodulators monotherapy was 0.99 (95%CI, 0.97-1.00, I 2 =0%). The pooled seroconversion rate in patients on anti-TNF monotherapy was 0.98 (95%CI, 0.94-0.99, I 2 =89%). With the use of a combination therapy of anti-TNF with thiopurines, the pooled seroconversion rate was 0.94 (95%CI, 0.83-0.98, I 2 =79%). The pooled seroconversion rates in patients on vedolizumab (0.98, 95%CI, 0.93-0.99, I 2 =90%) and ustekinumab (0.99, 95%CI, 0.98-0.99, I 2 =0%) were good. The pooled seroconversion rate in patients on JAK inhibitors (JAKi)was 0.97 (95%CI, 0.87-0.99, I 2 =0) ( Figure 3 ). The pooled relative risk of seroconversion was similar in the combination group as compared to anti-TNF alone (Pooled RR-0.98, 95%CI, 0.95-1.01, I 2 =69%) (Supplementary Figure 7) in eight included studies.

Five studies reported T cell responses after COVID-19 vaccination of which four reported SARS-CoV-2 specific responses. Two studies suggested that T cell responses could be attenuated with the use of immunomodulators while one study suggested that anti-TNF agents could augment T cell responses. Two studies suggested that the antibody response and T cell responses could be decoupled from each other (Supplementary Table 6 ).

The durability of serological response was reported in 9 studies at variable times after the complete vaccination ( Table 2) . Most of the studies suggested that titers fall after 4 weeks of COVID-19 vaccination. There was variability in the rate of decay with some of the studies clearly suggesting that the decay was faster in those treated with anti-TNF agents, immunomodulators or their combination.

Only two studies reported response to the third dose after the initial series of complete vaccination. 29, 48 Both studies reported that a majority of non-responders seroconverted after the third dose. Further the antibody titers also increased after the third dose (Supplementary Table  7 ).

Total of 12 studies reported breakthrough infections after COVID-19 vaccination in patients with IBD, however only five provided corresponding breakthrough infections in vaccinated controls. The pooled rate of breakthrough infections (12 studies, 36207 patients) was 0.01 (95%CI, 0.00-0.01, I 2 =98%) ( 

The visual assessment of the Funnel plot (Supplementary Figure 8 ) and the Egger test (t = 1.09, P = .2822) did not suggest presence of publication bias. The risk of bias assessment is depicted in Supplementary Table 8 and 9 . Few studies had concern regarding description of the selected sample size with lack of clear details. While certain studies did not look into the confounding factors of vaccine breakthrough infections. As the Joanna Briggs guidance suggests against using a score cut-off for quality assessment, we also did not score the studies.

The Baujat plot (Supplementary Figure 9 ) constructed for studies reporting seroconversion after two doses of COVID19 vaccines suggested that studies by Knezevic T et al and Kappleman MD et al contributed highest to the heterogeneity. 29, 33 The report by Knezevic et al is published as a conference abstract from Serbia and reports seroconversion after two doses of multiple types of vaccines including mRNA (Pfizer-BioNTech), AAV (AstraZeneca/ ChAdOxl nCoV-l9 COVISHIELD) and inactivated vaccines (SARS-CoV-2 Vero Cell, SPUTNIK V Gam-COVID-Vac). 33 The seroconversion rates after inactivated vaccines were particularly low. Subgroup analysis with vaccine subtypes showed lesser heterogeneity for analysis of Ad26.COV2.S (Janssen) and mRNA-1273 (Moderna) vaccines but high for the ChAdOx1-S (AstraZeneca) and BNT162b2 (Pfizer) types (Supplementary Figure 1) .

This systematic review provides the estimates of seroconversion after complete vaccination for COVID-19 in patients with IBD. We have also provided the pooled seroconversion rates among individual vaccines. The present study also reports about the durability of complete vaccination as well as efficacy of vaccination in preventing breakthrough infections. The overall data suggests that the seroconversion rates after two doses of COVID-19 vaccination in the IBD population was slightly lower than healthy controls. With m-RNA vaccines, the pooled rates of seroconversion were similar in patients of IBD as that of controls. The findings provide reassurance to patients with IBD and clinicians treating them regarding the seroconversion after complete vaccination for most vaccines. 61, 62 The other important finding is the impact of drugs on seroconversion rates: the rates of seroconversion were statistically similar among various drugs. The pooled seroconversion rates were numerically lower for steroids and combination of anti-TNF with immunomodulator. However, even these were >90% after complete vaccination. Anti-TNF agents, vedolizumab, ustekinumab, and JAK inhibitors were associated with good seroconversion rates with complete vaccination. The impact of anti-TNF agents on efficacy of COVID-19 vaccination has been under increasing scrutiny because of lower titers achieved in patients on these drugs and an early decay of titres. 30, 37 Recent data also suggests that the antibody titers may be lower in JAK inhibitors. 63 Interestingly, our analysis did not demonstrate any decreased seroconversion with the use of combination of anti-TNF with immunomodulators as compared to anti-TNF alone. This finding contrasts with results of a previous systematic review in the setting of IMIDs. 2 There could be many possible reasons for this finding: low number of studies and differences in the immunomodulator use in IBD as compared to other IMIDs.

The durability of antibody response following COVID-19 complete vaccination is a matter of ongoing evaluation. The systematic review suggested that there is decay in antibody responses after COVID vaccination in patients of IBD. The decay was faster in those treated with anti-TNF agents, immunomodulators or their combination. 20, 37, 45, 60 The biology behind this waning immunity needs further study of the mechanisms involved. The analysis on breakthrough infections suggested that the breakthrough infections could occur but the overall frequency was likely to be similar to the general population. This finding, along with the fact that the majority of breakthrough infections did not require hospitalization, is reassuring to IBD patients and carers. 32 There has been considerable debate about whether seroconversion is a proxy indicator of protection from breakthrough infections and severe COVID-19. In this regard functional assays to detect neutralizing antibodies have been considered as surrogates of protection. These tests could be viral neutralization assays, pseudo-virus neutralization assays or competitive viral neutralization tests. The pooled rates of positivity in neutralization assays after complete vaccination were also lower in patients of IBD as compared to healthy controls. Because of the lower number of participating studies, a subgroup analysis regarding the impact of various IBD therapies on neutralization was not possible.

T cell responses are believed to be an important component of protective response against the SARS-CoV-2 infection. These responses have been associated with protection from infection and severe disease. It is believed that they may be responsible for protection from emerging variants, even in situations where neutralizing response is not robust. 64 The importance of T cell response may be particularly important in individuals with decaying antibody titers and these may afford durable protection. 65 Interestingly the T cell response could be discordant to the antibody responses. 36 Unexpectedly, anti-TNF therapy seemed to augment T cell responses suggesting that even though these individuals may have attenuated antibody response, the protection may not be compromised. 36 There were only limited studies reporting the response rates of additional doses of COVID-19 vaccine in IBD. There is some evidence to suggest those who didn't have seroconversion following complete vaccination, did so after a booster dose. The seroconversion as well durability of antibody responses following the additional dose requires further studies.

With the third dose of BNT162b2 vaccine having good neutralization against newer variants like omicron in the general population, it would be worthwhile to see for responses in patients of IBD. 66 Chen et al reported reduction in neutralizing antibodies and Fc effector functions capacity in patients with anti-TNF therapy. 19 They found reduced neutralization of BNT162b2 m-RNA vaccine against B.1.617.2 (Delta strain) as compared to B.1.351 (Beta strain) in a cohort of chronic inflammatory diseases which included a subset of patients with Crohn's disease. 19 Our meta-analysis has certain limitations including a significant amount of heterogeneity. The multitude of factors which impact the seroconversion could be responsible for the high heterogeneity: differences in populations (type of IBD, age, drug therapies, disease activity and severity), type of vaccine (AAV, mRNA or both), definition/ assessment of seroconversion and the timing of determination of outcomes (time of follow-up for breakthrough infections, time from vaccination to the estimation of antibody responses). We attempted to address the heterogeneity by doing a subgroup analysis for the vaccine type and drug specific analysis. Other limitations include the small number of studies for some of the analysis (comparison of seroconversion with healthy controls, breakthrough infections and positivity of neutralization assays when compared to controls). Due to the small number of available studies, the T cell responses could not be analyzed quantitatively. Another limitation is that not all the data is from peer reviewed publications: preprints and conference abstracts have been included to include all the relevant information. Even with the limitations, the analysis includes a significant number of Tables   Table 1: Characteristics of studies included in the meta-analysis along with details on participants and vaccination Table 2 : Studies reporting durability of COVID vaccination in IBD 

Review of COVID-19 vaccine subtypes, efficacy and geographical distributions

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Risk and outcomes of coronavirus disease in patients with inflammatory bowel disease: A systematic review and meta-analysis. United

Antibody Response after 2 and 3 doses of SARS-CoV-2 mRNA Vaccine in Allogeneic Hematopoietic Cell Transplant Recipients

Immunogenicity and risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection after Coronavirus Disease 2019 (COVID-19) vaccination in patients with cancer: a systematic review and meta-analysis

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R Core Team R: A language and environment for statistical computing R Foundation for Statistical Computing

Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and incidence data

JBI Manual for Evidence Synthesis

Bias in meta-analysis detected by a simple, graphical test

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Reduced antibody activity against SARS-CoV-2 B.1.617.2 Delta virus in serum of mRNA-vaccinated patients receiving Tumor Necrosis Factor-α inhibitors

Antibody response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease -results of a single-center cohort study in a tertiary hospital in Germany

Antibody Responses to SARS-CoV-2 After Infection or Vaccination in Children and Young Adults With Inflammatory Bowel Disease

Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study

P040 Reduced serological response to COVID-19 vaccines in patients with IBD is further diminished by TNF inhibitor therapy; Early results of the VARIATION study (VAriability in Response in IBD Against SARS-COV-2 ImmunisatiON)

Lower Serologic Response to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases Treated with Anti-TNFα

Antibody Response Six Months after SARS-CoV-2 mRNA Vaccination in Patients with Inflammatory Bowel Disease

Immune Response Induced by SARS-CoV-2 Vaccines in Patients With Inflammatory Bowel Disease Under Biologic Therapy

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Factors Affecting Initial Humoral Immune Response to SARS-Cov-2 Vaccines among Patients with Inflammatory Bowel Diseases

Contributors to the CLARITY IBD study. Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD

Safety And Effectiveness Of The Bnt162b2 Mrna Covid-19 Vaccine In A Nationwide Cohort Of Patients With Inflammatory Bowel Disease

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S775 Seroprevalence of COVID-19 in Patients With Inflammatory Bowel Disease Under Biologic Treatment

S805 SARS-CoV-2 Vaccine Antibody Response in Patients With IBD

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P417 Seroconversion after COVID-19 Vaccination in Inflammatory Bowel Disease Patients

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Humoral Immune Response to Messenger RNA COVID-19 Vaccines Among Patients With Inflammatory Bowel Disease

P244 COVID-19 vaccine does not increase the likelihood of disease exacerbation in IBD: results from a population-based study

P354 Immunological response to vaccination against SARS-COV-2 infection in Inflammatory Bowel Disease patients under immunosuppressive therapy: should we prioritize an additional booster injection?

Impairment of CD4+ T and Memory B Cell Responses but Normal Memory CD8+T-Cell Activation on Crohn's Disease after COVID-19 Vaccination: A Twin Case

P307 The effect of COVID-19 infection and vaccination in patients with Inflammatory Bowel Disease and Irritable Bowel Syndrome, Journal of Crohn's and Colitis

Antibody response to the BNT162b2 SARS-CoV-2 vaccine in paediatric patients with inflammatory bowel disease treated with anti-TNF therapy

COVID-19 Vaccination in Patients With Inflammatory Bowel Disease and History of Reaction to Injectable Therapies

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P058 Impact of Inflammatory Bowel Disease Treatment and Risk of Covid-19 Infection after Full Immunization: A Nationwide Analysis

on behalf of the T2B! immunity against SARS-CoV-2 study group, DOP27 Humoral immune response after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases treated with immunosuppressive therapy -a Target to B! study

We searched PubMed, Embase, Conference abstracts and preprint servers for previous meta-analyses on responses to COVID-19 vaccination in patients with inflammatory bowel diseases (IBD). We identified two systematic reviews and meta-analyses which focused on seroconversion in patients with immune mediated inflammatory diseases (IMIDs) but none in the setting of IBD. These systematic reviews identified certain therapies which could attenuate responses to COVID-19 vaccination including B cell depleting agents and ant-CTLA-4 agents. These agents, are however, not typically used in IBD.

Our study provides the first estimates on the seroconversion rates after complete COVID-19 vaccination in IBD patients. Through this systematic review, comprising 46 studies, we report about the pooled seroconversion rates, positivity of neutralization assays, breakthrough infections in IBD patients and compare these to the control groups. Based on 31 studies with 9447 participants the overall seroconversion after complete vaccination was good (0.96, 95% CI, 0.94-0.97) but slightly lower than the controls (0.98, 95%CI, 0.98-0.99). The positivity of neutralization assays was lower in IBD patients as compared to the controls. Certain drugs like steroids and combination of anti-TNF with immunomodulators were associated with numerically (but not statistically) lower rates of seroconversion in contrast to excellent seroconversion amongst patients on no treatment or those on anti-TNF alone, vedolizumab, ustekinumab or JAK inhibitors.The studies reporting on durability suggested that titers begin declining 4 weeks after complete vaccination and the decay may be faster with anti-TNF, immunomodulators and combination of these two.

Our findings suggest that complete COVID-19 vaccination has good seroconversion in patients with IBD. However, durability of these responses is a concern especially with anti-TNF and immunomodulators. In the subset of non-responders to initial series of complete vaccination, an additional dose helps achieve serological response in most of them.