SARS-CoV-2-neutralizing humoral IgA response occurs earlier but modest and diminishes faster compared to IgG response.

Secretory immunoglobulin A (IgA) plays a crucial role in the mucosal immunity for preventing the invasion of the exogenous antigens, however, little has been understood about the neutralizing activity of serum IgA. Here, to examine the role of IgA antibodies against COVID-19 illnesses, we determined the neutralizing activity of serum/plasma IgG and IgA purified from previously SARS-CoV-2-infected and COVID-19 mRNA-vaccine-receiving individuals. We found that serum/plasma IgA possesses substantial but rather modest neutralizing activity against SARS-CoV-2 compared to IgG with no significant correlation with the disease severity. Neutralizing IgA and IgG antibodies achieved the greatest activity at approximately 25 and 35 days after symptom onset, respectively. However, neutralizing IgA activity quickly diminished and went down below the detection limit approximately 70 days after onset, while substantial IgG activity was observed till 200 days after onset. The total neutralizing activity in sera/plasmas of those with COVID-19 largely correlated with that in purified-IgG and purified-IgA and levels of anti-SARS-CoV-2-S1-binding IgG and anti-SARS-CoV-2-S1-binding IgA. In individuals who were previously infected with SARS-CoV-2 but had no detectable neutralizing IgA activity, a single dose of BNT162b2 or mRNA-1273 elicited potent serum/plasma neutralizing IgA activity but the second dose did not further strengthen the neutralization antibody response. The present data show that the systemic immune stimulation with natural infection and COVID-19 mRNA-vaccines elicit both SARS-CoV-2-specific neutralizing IgG and IgA response in serum, but the IgA response is modest and diminishes faster compared to IgG response. Author SummaryImmunoglobulin A (IgA) is the most abundant type of antibody in the body mostly located on mucosal surfaces as a dimeric secretory IgA. Such secretory IgA plays an important role in preventing the adherence and invasions of foreign objects by its neutralizing activity, while monomeric serum IgA is thought to relate to the phagocytic immune system activation. Here, we report that individuals with the novel coronavirus disease (COVID-19) developed both systemic neutralizing IgG and IgA active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the neutralizing IgA response was quick and reached the highest activity 25 days post-symptom-onset, compared to 35 days for IgG response, neutralizing IgA activity was modest and diminished faster than neutralizing IgG response. In individuals, who recovered from COVID-19 but had no detectable neutralizing IgA activity, a single dose of COVID-19 mRNA-vaccine elicited potent neutralizing IgA activity but the second dose did not further strengthen the antibody response. Our study provides novel insights into the role and the kinetics of serum IgA against the viral pathogen both in naturally-infected and COVID-19 mRNA-vaccine-receiving COVID-19-convalescent individuals.

Correlates of Neutralizing/SARS-CoV-2-S1-binding Antibody Response with Adverse Effects and Immune Kinetics in BNT162b2-Vaccinated Individuals

BackgroundWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the features of immune response remain to be clarified. MethodsIn the present prospective observational study, 225 healthy individuals in Kumamoto General Hospital, Japan, who received two BNT162b2 doses in February 2021, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions and live target cells) with SARS-CoV-2-S1-binding-IgG and -IgM levels, adverse effects (AEs), ages, and genders were examined. The average half-life of neutralizing activity and the average time length for the loss of detectable neutralizing activity were determined and the potency of serums against variants of concerns was also determined. FindingsSignificant rise in NT50s was seen in serums on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation was seen between NT50s and AEs. NT50s and IgG levels on day 28 post-1st dose and pain scores following the 2nd shot were greater in women than in men. The average half-life of neutralizing activity in the vaccinees was approximately 67.8 days and the average time length for their serums to lose the detectable neutralizing activity was 198.3 days. While serums from elite-responders (NT50s>1,500-fold: the top 4% among all participants NT50s) potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain. InterpretationBNT162b2-elicited immune response has no significant association with AEs. BNT162b2-efficacy is likely diminished to under detection limit by 6-7 months post-1st shot. High-level neutralizing antibody-containing serums potently to moderately block the infection of SARS-CoV-2 variants; however, a few moderate-level neutralizing antibody-containing serums failed to do so. If BNT162b2-elicited immunity memory is short, an additional vaccine or other protective measures would be needed. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the salient features of immune response including the persistence of protection remain to be clarified. There is a report that anti-SARS-CoV-2 antibodies persist through 6 months after the second dose of mRNA-1273 vaccine (Doria-Rose et al. N Engl J Med. 2021;384:2259-2261); however, more definite immune kinetics following mRNA-vaccine-elicited protection have to be clarified. The mRNA-vaccine-elicited protection against SARS-CoV-2 variants are also to be determined. Added value of this studyIn the present prospective study, 225 twice-BNT162b2-dose-receiving individuals in Japan were enrolled. No significant correlation was seen between 50% neutralizing titers (NT50s), determined by using infectious SARS-CoV-2 virions and live target cells, and adverse effects. Largely, NT50s and IgG levels were greater in women than in men. Following 28 days post-2nd shot, significant reduction was seen in NT50s, IgG, and IgM levels. The average half-life of NT50s was [~]68 days and the average time-length for participants serums to lose the detectable activity was [~]198 days. Although serums from elite-responders potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain. Implications of all the available evidenceBNT162b2 efficacy is likely to be diminished to under detection limit by 6-7 months post-1st shot on average. Individuals with moderate NT50s may fail to block beta variants. If BNT162b2-elicited immune memory is lost soon, additional vaccine(s) or other protective means would be needed.

Report on the Toronto International Program to Strengthen Family Medicine and Primary Care / 日本プライマリ・ケア連合学会誌

We participated in TIPS-FM (Toronto International Program to Strengthen Family Medicine and Primary Care) for two weeks in Toronto in June 2019. This program enabled us to learn many important factors for developing family medicine. Based on Canadian family medicine, which has a long history, we were able to review the missions of family medicine in Japan, and gained further insight into multilayered essentials on the patient-, community-, and global-levels.

Referral and Consultation Practice between Generalists and Specialists at a University Hospital: A Retrospective Cross-Sectional Study / 日本プライマリ・ケア連合学会誌

Background: Few studies have focused on the current state of referral and consultation practice between generalists and specialists at Japanese university hospitals.Methods: We retrospectively analyzed the electronic medical records of 513 outpatients (a cumulative total of 608 patients) who visited the Department of General Medicine of Toyama University Hospital between January and December 2016. All patients used our in-hospital consultation and referral service.Results: We referred 492 new patients to different specialists, with 40% referred to psychiatry, orthopedics, otolaryngology, and dermatology specialists. Our suspected diagnoses were correct for 285 of 395 patients (72%) who were referred to specialists to confirm the diagnosis. No abnormalities were observed in 86 patients (21%), and inappropriate referrals were made for 5 patients (1.2%). We also received 116 consultations from specialists, 66% of which were from orthopedics, psychiatry, gynecology, oral dental surgery, and neurosurgery specialists. Many of the referred patients had vague symptoms such as fever and general fatigue.Conclusion: Improving the practical skills of generalists regarding orthopedic and otolaryngologic problems may result in more appropriate referrals. Our department also served as a consultant for medical problems for specialists, especially orthopedic surgeons and psychiatrists.

Case of delirium and convulsion after administration of olanzapine in a cancer patient with refractory vomiting

<b>Purpose:</b> We report a case of delirium and convulsion after administration of olanzapine in a cancer patient with refractory vomiting. <b>Case report:</b> The patient was a male in his 70s who suffered from lung cancer. After chemotherapy, olanzapine was used for refractory nausea and vomiting. Since this treatment, the patient has experienced delirium and convulsions. While we modified some reversible causes of the delirium, the delirium did not improve. Discontinuation of olanzapine resulted in improvement of the delirium. Recurrent convulsions did not occur with sodium valproate. Olanzapine might increase the risk of delirium and convulsions.