Day: 09/03/2022

Gallbladder Volvulus

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An 86-year-old woman presented to the emergency department with a 1-day history of nausea, vomiting, and pain on the right side of her abdomen. Her vital signs were normal. On physical examination, there was tenderness in the right upper quadrant, with a positive Murphy’s sign and involuntary guarding. The results of laboratory studies were normal. Computed tomography of the abdomen and pelvis revealed a distended gallbladder with a thickened wall outside the gallbladder fossa (Panel A, arrow). There was also swirling of the cystic artery and duct (Panel B, arrow) but no dilatation of the common bile duct. Gallbladder volvulus was suspected, and the patient was taken to the operating room. The diagnosis was confirmed on laparoscopy when a free-floating, necrotic gallbladder was observed encircling the cystic artery and duct (Panel C). The surgery was converted to an open procedure, and detorsion and resection of the gallbladder were successfully performed (Panel D). Gallbladder volvulus occurs when the gallbladder twists along the axis of the cystic artery and duct, compromising blood flow to the organ. Patients present with an acute abdomen, and the cause may be difficult to diagnose preoperatively. This patient did well after surgery and was discharged on postoperative day 2.

Rice Bodies in Tenosynovitis Due to Psoriatic Arthritis

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A 74-year-old woman presented to the infectious diseases clinic with a 4-year history of swelling of the fifth finger on the left hand. She had a history of psoriatic arthritis that had been treated with a tumor necrosis factor inhibitor and methotrexate. On physical examination of the left hand, there was redness and swelling from the metacarpophalangeal joint to the distal interphalangeal joint in the proximal and middle phalanges of the fifth digit; the redness and swelling extended across the palm, with predominant involvement in the hypothenar region (Panel A). Flexion of the fifth finger was limited. There were also nontender, mobile, subcutaneous nodules in the hypothenar region and over the proximal fifth finger. Magnetic resonance imaging of the left hand revealed tenosynovitis of all flexor tendons. A carpal-tunnel release and fifth-finger flexor tenosynovectomy were performed. After incision of the transverse carpal ligament, numerous “rice bodies” — grainlike particles that form in joints in the context of infectious or noninfectious chronic inflammation — were found in the carpal tunnel (Panel B). More rice bodies were released after the fifth-finger tendon sheaths were incised. Microbiologic and molecular studies were negative for bacteria, fungi, and mycobacteria. Histopathological testing showed papillary synovial hyperplasia with chronic inflammation and fibrinous nodules. A final diagnosis of inflammatory tenosynovitis with rice bodies associated with psoriatic arthritis was made. Treatment with oral glucocorticoids was initiated. At 6 weeks of follow-up, the patient’s symptoms had abated.

Tongue Telangiectasias in Systemic Sclerosis

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A 61-year-old woman with primary biliary cholangitis and a 1-year history of Raynaud’s phenomenon was referred to the rheumatology clinic for further evaluation and treatment. She reported a long-standing history of swollen fingers but no finger ulcerations, joint pain or swelling, dyspnea on exertion, dysphagia, or heartburn. On physical examination, telangiectasias were seen on the palms and the volar aspect of the fingers and on the tongue. There was no tightening of the perioral skin. The fingers were puffy and without sclerodactyly. Punctate hemorrhages of the nailfold capillaries were also noted, and a subsequent nailfold capillaroscopy confirmed capillary enlargement with pericapillary hemorrhage. The patient tested positive for anticentromere antibodies and negative for autoantibodies against topoisomerase I. A diagnosis of limited cutaneous systemic sclerosis was made. In systemic sclerosis, telangiectasias may be seen on the oral mucosa, as well as on the hands, face, and upper torso. Given this, an oral examination is an important part of the assessment. On further evaluation of this patient, no pulmonary hypertension or interstitial lung disease was noted. Treatment for symptoms of Raynaud’s phenomenon was initiated. At a 3-year follow-up, the symptoms of Raynaud’s phenomenon had abated but the patient’s telangiectasias remained.

Subacute Combined Degeneration from Nitrous Oxide Use

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A 32-year-old man presented to the emergency department with a 6-week history of tingling in his arms and legs and a 2-week history of inability to walk. Two months before presentation, he had begun inhaling nitrous oxide — also known as “whippets” or “laughing gas” — daily. On physical examination, the Romberg test was positive, and sensory ataxia, impaired proprioception and vibratory sensation, and preserved nociception were noted. Magnetic resonance imaging of the whole spine showed hyperintensity in the posterior spinal cord from C1 to T12 on T2-weighted images (Panel A, asterisks). Axial images revealed a lesion in the dorsal column that was hyperintense on both T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequence, a finding known as the “inverted-V sign” that is seen in subacute combined degeneration (Panel B, arrow and inset). The patient’s vitamin B12 level was 107 pg per milliliter (reference value, >231). There was no macrocytic anemia. Antibody testing for autoimmune gastritis was negative. A diagnosis of subacute combined degeneration associated with nitrous oxide use was made. Long-term use of nitrous oxide causes the inactivation of vitamin B12, which then interrupts methionine synthase activity. After the patient ceased nitrous oxide use and received treatment with cyanocobalamin injections for 2 weeks, his vitamin B12 level normalized. At the 4-week follow-up, he was able to walk independently.

Dietary flavonoids may mitigate some risk for smoking-related COPD

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Higher intake of dietary flavonoids may mitigate some risk for COPD in current and former smokers, according to a study published in European Respiratory Journal.

“Fruit and vegetables, as well as tea, cocoa and other plant-based foods and beverages, are dietary sources of flavonoids, which are bioactive compounds that reduce oxidative stress and systemic inflammation,” Nicola P. Bondonno, PhD, apostdoctoral research fellow at the School of Medical Health Sciences at Edith Cowan University in Perth, Australia, and colleagues wrote. “… Although epidemiological studies investigating the association between flavonoid intakes specifically and COPD are missing, there is some evidence that flavonoid intakes are favorably associated with pulmonary function parameters and less age-related decline in lung function.”

High intake of dietary flavonoids was associated with
Data were derived from Bondonno NP, et al. Eur Respir J. 2022;doi:10.1183/13993003.02604-2021.

The prospective cohort study included 55,413 participants in Denmark without COPD aged 50 to 65 years at baseline (mean age, 56 years; 47.6% men). Flavonoid intakes were estimated using a food frequency questionnaire. Daily median flavonoid intake was 496 mg.

During a median follow-up of 21 years, 5,557 participants were diagnosed with COPD, of whom 4,013 were current smokers, 1,062 were former smokers and 482 were never smokers.

Participants with the highest total flavonoid intakes had a 20% lower risk for COPD compared with participants with the lowest intakes in multivariable analyses (HR = 0.8; 95% CI, 0.74-0.87). In addition, in each flavonoid subclass, researchers identified a 6% to 22% lower risk for COPD.

The researchers reported that the inverse association between flavonoid intake and risk for COPD remained among men and women, but only among current smokers (HR = 0.77; 95% CI, 0.7-0.84) and former smokers (HR = 0.82; 95% CI, 0.69-0.97), not never smokers. In addition, higher flavonoid intakes appear to have lessened the higher risk for COPD associated with smoking intensity, according to the researchers.

“While the findings of this study suggest an importance of dietary flavonoids in partially mitigating the risk of COPD in people who smoke, both current and former smokers remained at a substantially higher risk of COPD than nonsmokers, indicating that dietary modifications should be secondary to smoking cessation,” the researchers wrote.

Early-term births associated with ADHD symptoms

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Children born before 39 weeks are more likely to experience symptoms related to ADHD, according to data published in The Journal of Pediatrics.

Co-author Nancy E. Reichman, PhD, is a professor in the neonatology division at Robert Wood Johnson Medical School at Rutgers University. Reichman told Healio that although she had long been interested in infant health, in recent years she became interested in how children develop later in life.

IDC0822Reichman_Graphic_01

“I was involved with the data collection for the Fragile Families and Child Wellbeing study,” Reichman said. “I knew that the data were excellent for looking at linkages between prenatal or birth factors and how kids are doing later. One of the unique aspects of these data were the inclusion of teacher reports of how kids are doing, which sometimes, it could be argued, are more objective, perhaps, than maternal reports.”

Reichman and colleagues limited their study to full-term infants (born at 37 to 41 weeks) “because that is a range that has not been considered particularly at risk for adverse longer term outcomes,” she explained.

In an analysis of 1,400 children included in the aforementioned Fragile Families and Child Wellbeing study, the researchers used the survey reports of the children’s teachers at age 9, which included ratings on symptoms of hyperactivity, ADHD, oppositional behavior and cognitive problems or inattention.

Although Reichman said she and her co-authors expected there would be “a continuation of the generalized pattern between gestational age and ADHD symptoms (ie, it is known that preterm children are at risk),” she added that they were “a bit surprised with the strength of the associations within the full-term period.”

The researchers found that every week gestational age at term was associated with 6% lower hyperactivity scores, as well as 5% lower ADHD and cognitive problems or inattention scores. Birth at 37 to 38 weeks was associated with 23% higher hyperactivity scores and 17% higher ADHD scores when compared with birth at 39 to 41 weeks.

“The findings suggest that regular screenings for ADHD symptoms are important for children born at 37 to 38 weeks,” Reichman said in a press release.

She also told Healio that “the risk doesn’t just stop after 37 weeks.”

“It doesn’t mean that if you’re if your child is born at 37 or 38 weeks that they’re going to have any problems, but sometimes this group might be overlooked, and overlooked in terms of the screenings, compared to preterm kids,” Reichman said.

Earlier CRC screening with colonoscopy, FIT cost-effective ‘irrespective of BMI’

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Regardless of patient sex or BMI, initiating colorectal cancer screening with colonoscopy at age 45 years or with fecal immunochemical testing at age 40 years was cost-effective, according to new research.

In addition, researchers reported CRC screening with colonoscopy at age 40 years was cost-effective in men with class 2 and 3 obesity, whom investigators noted have the highest risk for CRC and all-cause mortality.

study data

“Initiating CRC colonoscopy-based screening at age 45 years is likely to be cost-effective for women and men irrespective of BMI, initiating colonoscopy-based screening at age 40 years may be cost-effective in men with obesity [class 2 to 3], and FIT-based screening may be cost-effective starting at age 40 years in both sexes across the range of BMI,” Aaron Yeoh, MD, and colleagues from the division of gastroenterology and hepatology at Stanford University School of Medicine, wrote in Clinical Gastroenterology and Hepatology.

As obesity is a suspected risk factor for CRC, researchers sought to determine whether intensified CRC screening would be cost-effective in overweight and obese individuals, noting that obesity also is associated with increased morbidity and mortality risks and incremental costs. “Given these competing risks, our aim was to estimate the potential clinical impact and cost-effectiveness of earlier initiation or more intensive CRC screening in overweight and obese persons,” they wrote.

Using a decision analytic model that was recalibrated to avoid double-counting the impact of BMI and birth cohort effect of increasing CRC incidence at younger ages, investigators compared CRC screening initiated at ages 45 or 40 years vs. 50 years in men and women with BMI that ranged from normal weight to class 3 obesity.

They analyzed 10 cohorts, grouped by age and BMI, and studied the impact of annual fecal immunochemical testing (FIT) and colonoscopy every 5 and 10 years. Incremental costs and quality of life-years (QALY) gained were calculated using a payer perspective, with cost-effectiveness defined as no more than $100,000/QALY gained.

Without CRC screening, investigators reported comparable sex-specific total CRC mortality for individuals who were overweight or had class 1 to 3 obesity, “reflecting the counterbalancing of higher CRC risk by lower life expectancy as BMI rises.”

Across BMI categories and sex groups, initiating colonoscopy at age 45 vs. 50 years with routine screening every 10 years through age 75 years cost $33,400 to $85,900/QALY gained. However, researchers reported starting screening at age 40 vs. 45 years with subsequent colonoscopies at 10-year intervals was only cost-effective for men with class 2 or 3 obesity ($93,300/QALY gained vs. $80,400/QALY gained, respectively). In addition, starting FIT at age 40 vs. 45 years cost $22,000/QALY to $58,800/QALY gained for both sexes and across BMI groups.

“Our finding that initiating CRC screening at age 45 years appears cost-effective across

the range of BMI groups, and that even earlier initiation at age 40 years appears cost-effective in men with obesity [class 2 to 3], suggests that the benefits of earlier CRC screening are substantial even when the higher CRC risks in overweight and obese persons are balanced against the higher risk of competing morbidity and mortality, and overweight- and obesity-associated costs that are incurred when CRC death is averted,” researchers wrote. “These findings have implications for CRC screening in overweight and obese persons specifically, and for risk-adjusted CRC screening more generally.”

Air pollution exposure may drive heart attack risk for nonsmokers

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Among nonsmokers, data showed a link between higher concentrations of air pollution and greater MI incidence in Germany, researchers reported at the European Society of Cardiology Congress.

“The correlation between air pollution and heart attacks in our study was absent in smokers,” Insa de Buhr-Stockburger, MD, of Berlin Brandenburg Myocardial Infarction Registry, said in a press release. “This may indicate that bad air can actually cause heart attacks since smokers, who are continuously self-intoxicating with air pollutants, seem less affected by additional external pollutants.”

Exhaust pollution_246771116
Source: Adobe Stock

De Buhr-Stockburger and colleagues analyzed data from 17,873 MI cases from 2008 to 2014, using the Berlin Brandenburg Myocardial Infarction Registry, as well as detailed regional air pollution data provided by the BLUME network, including daily levels of nitric oxide and particulate matter with a diameter of less than 10 µm (PM10), grouped by region (downtown, main roads, suburbs). Preceding days (single and 3-day average) were also assorted to every single day. Researchers also assessed ambient temperature, precipitation and sunshine duration from the Berlin-Tempelhof weather station.

The researchers analyzed associations between the incidence of acute MI and average pollutant concentrations on the same day, the previous day and an average of the 3 preceding days among all patients and according to baseline characteristics.

Researchers found MI was significantly more common on days with high nitric oxide concentrations, with a 3.2% higher incidence for every 10 µg/m3 increase on the same day (P < .001). MI was also more common when there was a high average PM10 concentration during the 3 preceding days, with a 4.8% higher incidence for every 10 µg/m3 increase (P < .001).

Incidence of MI among smokers was unaffected by nitric oxide and PM10 concentrations. Researchers also observed that incidence of MI was related to the maximum temperature, with a 6% lower incidence for every 10°C rise in temperature (P < .001).

There were no associations with sunshine duration and precipitation.

“The study indicates that dirty air is a risk factor for acute myocardial infarction, and more efforts are needed to lower pollution from traffic and combustion,” de Buhr-Stockburger said in the release. “Causation cannot be established by an observational study. It is plausible that air pollution is a contributing cause of myocardial infarction, given that nitric oxide and PM10 promote inflammation, atherosclerosis is partly caused by inflammatory processes and no associations were found in smokers.”

Gallstone Ileus

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A 74-year-old woman with hypertension presented to the emergency department with a 3-day history of epigastric pain, nausea, vomiting, fever, chills, weakness, and poor appetite. She also reported having had no bowel movements or flatus for the past 2 days. Her blood pressure was 150/128 mm Hg, and her heart rate 144 beats per minute. An abdominal examination revealed tenderness in the periumbilical region and in the left lower quadrant, with voluntary guarding and rebound tenderness. There was no jaundice. Computed tomography of the abdomen revealed obstruction of the ileum caused by a gallstone (Panel A, arrow) and pneumobilia (Panel B, arrow). This combination of radiologic findings — an ectopic gallstone, small-bowel obstruction, and pneumobilia — is known as Rigler’s triad and aroused concern about gallstone ileus. Gallstone ileus is an uncommon cause of small-bowel obstruction, wherein a gallstone passes through a biliary–enteric fistula and becomes impacted within the intestinal lumen. The patient underwent a laparotomy, which confirmed gallstone ileus, and an enterotomy was performed to remove the gallstone (Panel C). Broad-spectrum antibacterial agents were administered after the procedure. The patient was discharged home on postoperative day 11 and was referred for an outpatient cholecystectomy.

Covid-19 Vaccines —Covid-19 Vaccines — Immunity, Variants, Boosters

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The coronavirus disease 2019 (Covid-19) pandemic has claimed an estimated 15 million lives, including more than 1 million lives in the United States alone. The rapid development of multiple Covid-19 vaccines has been a triumph of biomedical research, and billions of vaccine doses have been administered worldwide. Challenges facing the Covid-19 vaccine field include inequitable vaccine distribution, vaccine hesitancy, waning immunity, and the emergence of highly transmissible viral variants that partially escape antibodies. This review summarizes the current state of knowledge about immune responses to Covid-19 vaccines and the importance of both humoral and cellular immunity for durable protection against severe disease.

Antiviral Immunity

The immune system is broadly divided into the innate and adaptive immune systems. Innate immune responses are the first line of defense against viruses and are rapidly triggered when cellular pattern-recognition receptors, such as toll-like receptors, recognize pathogen-associated molecular patterns. Innate antiviral immunity includes secretion of type I interferons, antiviral cytokines, and certain cellular responses, including neutrophils, monocytes and macrophages, dendritic cells, and natural killer cells.1

Adaptive immune responses, the second line of defense against viruses, involve antigen-specific recognition of viral epitopes. Adaptive immunity includes two complementary branches of the immune system: humoral immunity and cellular immunity. Humoral immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) includes antibodies that bind the SARS-CoV-2 spike protein and either neutralize the virus or eliminate it through other effector mechanisms.2,3 Cellular immunity to SARS-CoV-2 includes virus-specific B cells and T cells, which provide long-term immunologic memory and rapidly expand on reexposure to antigen. B cells produce antibodies, CD8+ T cells directly eliminate virally infected cells, and CD4+ T cells provide help to support the immune responses.Figure 1. Immune Responses for Protection against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

For acute viral infections, including SARS-CoV-2, it is likely that neutralizing antibodies are critical for blocking acquisition of infection, whereas a combination of humoral and cellular immune responses most likely controls viral replication after infection and prevents progression to severe disease, hospitalization, and death (Figure 1).4-7 For a highly transmissible SARS-CoV-2 variant that largely escapes neutralizing antibodies, cellular immunity may be particularly important for long-term protection against severe disease.

Current Covid-19 Vaccines

Early data from nonhuman primate studies showed the protective efficacy of both natural immunity8 and vaccine immunity9-12 against experimental SARS-CoV-2 challenge. These findings provided preclinical support for the rapid clinical development of SARS-CoV-2 vaccines. The World Health Organization (WHO) reported that more than 300 Covid-19 vaccines were in preclinical or clinical development as of May 6, 2022. Ten Covid-19 vaccines, reflecting eight distinct vaccine products, have been approved by the WHO for global use (see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). These vaccines involve four distinct vaccine platforms: inactivated virus vaccines (Sinopharm’s Covilo, Sinovac’s CoronaVac, and Bharat Biotech’s Covaxin), messenger RNA (mRNA) vaccines (Moderna’s Spikevax mRNA-1273 and Pfizer–BioNTech’s Comirnaty BNT162b2), adenovirus vector–based vaccines (AstraZeneca’s Vaxzevria and Covishield ChAdOx1 and Johnson & Johnson–Janssen’s Ad26.COV2.S), and adjuvanted protein vaccines (Novavax’s Nuvaxovid and Covovax NVX-CoV2373). Additional vaccines have been approved by other regulatory bodies and are also in widespread clinical use, but a comprehensive summary of all Covid-19 vaccines is beyond the scope of this review. It has been estimated that global Covid-19 vaccination saved approximately 20 million lives during the first year of the vaccine rollout.

In the United States, four vaccines have been authorized for either full approval or emergency use: the mRNA vaccines BNT162b2 and mRNA-1273, the adenovirus vector–based vaccine Ad26.COV2.S, and most recently the adjuvanted protein vaccine NVX-CoV2373. Randomized, placebo-controlled, phase 3 trials in the United States, conducted before the emergence of the omicron variant, showed initial protective efficacy of 94 to 95% against symptomatic Covid-19 infection with the two-shot BNT162b2 vaccine, the two-shot mRNA-1273 vaccine, and the two-shot Ad26.COV2.S vaccine, as well as 72% efficacy with the one-shot Ad26.COV2.S vaccine14-17 (Table 1). The mRNA vaccines have been used most widely in the United States and Europe, but their use in developing countries has been relatively limited — in part because of their cost, freezing requirements, distribution logistics, and business priorities — and has resulted in stark global health inequities. More than 70% of eligible persons in the United States and most other developed countries have been fully vaccinated, whereas less than 15% of persons in Africa have been fully vaccinated (Figure 2). A more equitable vaccine rollout that achieved the WHO target of 40% vaccination coverage in developing countries in 2021 would have saved an estimated 600,000 lives.13 The adenovirus vector–based vaccines have greater stability than the mRNA vaccines and no freezing requirements and have been used more extensively in developing countries.

The Food and Drug Administration and the Centers for Disease Control and Prevention (CDC) have recently restricted the use of Ad26.COV2.S in the United States because of the rare but serious occurrence of vaccine-induced immune thrombotic thrombocytopenia (VITT), also called thrombosis with thrombocytopenia syndrome (TTS). VITT has developed in 54 persons (9 of whom died), reflecting a rate of 3 to 4 cases per 1 million vaccinated persons.19,20 However, adenovirus vector–based vaccines remain first-line vaccines in much of the developing world, and the rate of VITT may be lower in South Africa than in the United States.18,21,22 VITT has also been reported in Europe with ChAdOx1, at a rate of 13 to 39 cases per 1 million vaccinated persons.23,24 In the United States, VITT has also been reported in 3 patients who received mRNA-1273 (1 of whom died).19,25

Myocarditis and pericarditis have been reported as complications with BNT162b2 and mRNA-1273, at a rate of 52 to 137 cases per 1 million vaccinated adolescent boys and young men after the second dose,26-29 with at least 10 reported deaths.27,28,30,31 The incidence rate of myocarditis within 7 days after the second mRNA dose has been reported as 566 cases per 1 million person-years.32 Although most cases of vaccine-induced myocarditis are mild, severe complications can occur, and cardiac magnetic resonance imaging changes have been reported to persist in a substantial fraction of young men for at least 3 to 8 months after recovery.33 Both thrombosis and myocarditis occur far more frequently after Covid-19 infection than after Covid-19 vaccination.

Vaccine Durability

The BNT162b2 and mRNA-1273 vaccines induce outstanding short-term neutralizing antibody responses and protective efficacy.14,15 However, the high initial serum neutralizing antibody titers induced by mRNA vaccines wane by 3 to 6 months and decline further by 8 months, with a half-life of approximately 60 days.34-38 In contrast to BNT162b2 and mRNA-1273, Ad26.COV2.S induces lower initial neutralizing antibody titers,16,39,40 but these neutralizing antibody responses and clinical effectiveness are fairly durable for at least 8 months.38,41-43 At 6 to 8 months, antibody responses are fairly similar with BNT162b2, mRNA-1273, and Ad26.COV2.S.38,43 Data from real-world effectiveness studies are largely concordant with these immunologic data and have shown initially higher protection with BNT162b2 and mRNA-1273 than with Ad26.COV2.S, but these differences narrowed after several months.41,44-46 Thus, BNT162b2 and mRNA-1273 induce high initial antibody titers that wane after a few months, whereas Ad26.COV2.S induces lower initial antibody responses with greater durability.

The waning of immunity with mRNA vaccines is correlated with increased breakthrough infections in vaccinated persons, initially exemplified by the large cluster of breakthrough infections with the SARS-CoV-2 delta variant in July 2021 in Provincetown, Massachusetts.47 In vaccinated persons with breakthrough infections, particularly robust immune responses, known as hybrid immunity, have been shown to develop. These findings suggest that population immunity to SARS-CoV-2 will continue to increase through a combination of widespread vaccination and infection.48 Genomic and epidemiologic data from this outbreak showed evidence of transmission between fully vaccinated persons.49

Cellular immune responses are induced by both mRNA vaccines and adenovirus vector–based vaccines and have shown greater durability than serum antibody titers. Germinal center B cells have been reported to persist for at least 6 months after BNT162b2 vaccination.50,51 CD8+ T-cell responses are particularly high after Ad26.COV2.S vaccination, with durability for at least 6 to 8 months.38,52 Because CD8+ T-cell responses control viral replication after infection,4,6,53-55 it is likely that SARS-CoV-2 vaccines will continue to provide substantial protection against severe disease even after serum neutralizing antibody titers wane.

In immunocompromised persons, both antibody and T-cell responses to Covid-19 vaccines are reduced, with the degree of reduction dependent on the extent and type of immunosuppression.56,57 In these populations, additional vaccine doses and prophylactic treatment with monoclonal antibodies are recommended.

SARS-CoV-2 Variants of Concern

In the spring of 2020, the predominant global form of the original virus rapidly transitioned to a variant that carried four mutations in the SARS-CoV-2 genome, including a single D614G point mutation in the spike protein that conferred a fitness advantage.58,59 Subsequently, multiple waves of SARS-CoV-2 variants have emerged that replaced prior variants, with new variants often showing increased transmissibility and greater antibody escape (Figure 3). In late 2020, the alpha (B.1.1.7), beta (B.1.351), and gamma (P.1) variants emerged in the United Kingdom, South Africa, and Brazil, respectively. These variants were then replaced globally by the delta (B.1.617.2) variant, which emerged in India in the summer of 2021. In late 2021, the highly transmissible omicron (B.1.1.529) variant emerged in Africa and abruptly became the most prevalent virus globally. In contrast to the 4 mutations in delta, omicron has more than 50 mutations, including more than 30 mutations in the spike protein, which result in substantial escape from neutralizing antibody responses elicited by vaccination or prior infection with a non-omicron variant.60-64 The omicron lineage has rapidly splintered into subvariants BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4, and BA.5 (Figure 3). Neutralizing antibody titers against BA.5, which is currently the predominant variant in the United States, are decreased by a factor of approximately 3 as compared with titers against BA.1 and BA.2.65-67

Multiple studies have shown that neutralizing antibodies induced by all primary vaccine regimens show little cross-reactivity with omicron but that boosting leads to a substantial increase in omicron neutralizing antibodies.68,69 However, these increased neutralizing antibody titers, as well as clinical effectiveness, have been shown to wane by 4 months after a third mRNA immunization.62,70,71 After a fourth mRNA immunization, protection against infection with SARS-CoV-2 omicron has been reported to wane after just 4 weeks, although protection against severe disease lasts longer.72 Hybrid immunity from both vaccination and infection provides greater and more durable protection than either alone.73,74

In contrast with the limited cross-reactivity of vaccine-induced neutralizing antibodies to omicron, T-cell responses induced by vaccines have very good (>80%) cross-reactivity to omicron75-77 and to prior variants.6,39,53 These data suggest that cellular immunity to SARS-CoV-2 variants remains largely intact. During the omicron surge in South Africa, the two-shot Ad26.COV2.S and the two-shot BNT162b2 vaccines provided 72% and 70% protection against hospitalization and 82% and 70% protection against admission to an intensive care unit, respectively18 (Table 1). This robust protection, essentially in the absence of high titers of omicron neutralizing antibodies, suggests the importance of other immune measures, including CD8+ T-cell responses and possibly other functional antibody responses, in providing protection against severe disease with a viral variant that largely escapes neutralizing antibodies.Figure 4. Protective Efficacy of Covid-19 Vaccines in the United States.

In the United States, composite data from the CDC show that the BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines all provided substantial protection against the delta surge in the fall of 2021 and against the omicron surges in the winter of 2021–2022 and in the spring of 2022 (Figure 4). Breakthrough rates per 100,000 vaccinated persons were higher with Ad26.COV2.S than with the mRNA vaccines during the delta surge but were lower with Ad26.COV2.S than with the mRNA vaccines during the omicron surge, potentially reflecting the durability of Ad26.COV2.S-induced immunity. These data are consistent with real-world effectiveness studies that have shown that the mRNA vaccines are initially more effective than the Ad26.COV2.S vaccine but that these differences diminish or disappear after several months.18,41,44-46

Immune Correlates of Protection

Early preclinical studies in nonhuman primates identified both neutralizing and other functional antibodies as correlates of vaccine protection against SARS-CoV-2 challenge.8,9,12 Adoptive transfer studies with purified IgG confirmed that antibodies alone were sufficient to block infection in both nonhuman primates and hamsters, provided that the antibodies were administered at a sufficiently high dose.54,78,79

In vivo CD8 depletion studies in nonhuman primates also showed that CD8+ T cells contributed to protection when antibody titers were subprotective.54 Moreover, vaccine failure against an omicron challenge in nonhuman primates was associated with low levels of both omicron neutralizing antibodies and CD8+ T cells.80 These data suggest that antibodies alone can block infection if antibody titers against the infecting virus strain are sufficiently high but that a combination of humoral and cellular immunity is critical for virologic control after breakthrough infection.

Analyses of immune correlates from the phase 3 clinical trials of mRNA-1273 and Ad26.COV2.S confirmed that antibody titers correlated with protection against symptomatic Covid-19 infection.81,82 However, these studies were performed before the emergence of the omicron variant, and T-cell responses were not included in these correlate analyses. It is possible that correlates of protection against highly transmissible viral variants that largely escape neutralizing antibody responses, such as omicron, skew more heavily toward cellular immunity. Moreover, CD8+ T cells have been shown to correlate with survival among patients with Covid-19 and hematologic cancer.7 As discussed above, both BNT162b2 and Ad26.COV2.S provided robust protection against severe disease during the omicron surge in South Africa in the absence of high titers of omicron neutralizing antibodies.18 Moreover, Ad26.COV2.S provided protection against hospitalization and death during the beta and delta surges in South Africa in the absence of high titers of neutralizing antibodies against these variants.21

Taken together, these data suggest that neutralizing antibodies are primarily responsible for blocking acquisition of SARS-CoV-2 infection but that both antibody and CD8+ T-cell responses are critical for preventing severe disease (Figure 1). Current vaccines provide only modest protection against infection and transmission with the omicron variant, even at peak immunity after boosting. Moreover, it is likely that neutralizing antibody titers may need to be substantially higher to protect against infection with the highly transmissible omicron variant than were needed to protect against infection with prior variants. In contrast to neutralizing antibodies, vaccine-induced CD8+ T-cell responses are highly cross-reactive against omicron and most likely contribute substantially to protection against severe disease. Future research should focus on the role of mucosal humoral and cellular immunity at the site of inoculation, which may play a critical role in protection against SARS-CoV-2 infection.

Proposed Framework for Covid-19 Vaccine Boosters

The expectation that Covid-19 vaccines would prevent acquisition of infection and block onward transmission was based on initial data in 2020 (before the emergence of viral variants) that showed high neutralizing antibody titers and robust protective efficacy at peak immunity after mRNA vaccination. However, given the substantial waning of serum neutralizing antibody titers and the emergence of variants with increased transmissibility and antibody escape, it would be reasonable now to recalibrate goals for Covid-19 vaccines. Current vaccines may not provide high-level, sustained protection against infection or transmission with omicron, even after multiple boosts and also after the introduction of updated omicron-specific vaccines. Instead, the most important goal of Covid-19 vaccination should be to provide long-term protection against severe disease, hospitalization, and death from current and future variants.

Booster recommendations should therefore take into account not only peak neutralizing antibody titers but also durable prevention of severe Covid-19 disease. Such protection will probably require a combination of humoral and cellular immunity, with an emphasis on long-term rather than short-term immune responses. However, to date, the field has focused largely on short-term neutralizing antibody responses. The potential role of an omicron-containing booster is currently being explored, but a study in nonhuman primates showed that an omicron-specific mRNA vaccine was not better than the original mRNA-1273 vaccine for protection against omicron challenge.83 Early clinical studies have shown that boosting with bivalent mRNA vaccines containing both ancestral and omicron BA.1 spike immunogens induced peak omicron neutralizing antibody titers that were less than twice the peak titers induced by boosting with the original mRNA vaccines. Thus, clinical benefits of the updated boosters as compared with the current vaccines are not clear. Heterologous prime-boost (“mix-and-match”) regimens, which involve combinations of mRNA and Ad26 vaccines, are also being investigated as a strategy for improving the magnitude and durability of humoral and cellular immunity, as compared with either type of vaccine alone.52,84,85 In addition, early research on the development of pan-sarbecovirus and pan-betacoronavirus vaccines is under way.

Boosting every 4 to 6 months to maintain high serum neutralizing antibody titers may not be a practical or desirable long-term strategy. Boosting with mRNA vaccines is also not risk-free. Moreover, frequent boosting recommendations may worsen “booster fatigue” in the general population, given that to date only 47% of eligible persons in the United States have received any booster dose. Expert opinion on the benefits of frequent boosters remains divided, communications from public health authorities have been viewed as confusing and overpromising, and vaccine hesitancy remains a major challenge. Frequent booster recommendations may also distract from the critical goal of vaccinating the large number of unvaccinated persons in the United States and throughout the world and may further exacerbate global health inequities.

Plans for boosters should therefore be based on robust scientific data that show substantial and sustained increases in prevention of severe disease rather than on short-term increases in neutralizing antibody titers. Enhanced community engagement and implementation research may also reduce vaccine misinformation. Ideally, Covid-19 boosters should be recommended no more than annually and preferably less frequently, and a diversity of booster options should be available to the public. The use of vaccine platforms with improved durability would be highly desirable.

Conclusions

The Covid-19 pandemic appears to be transitioning from a hyperacute phase to an endemic phase. Current Covid-19 vaccines are less effective at blocking infection with the omicron variant than at blocking infection with prior variants, but protection against severe disease remains largely preserved. The primary goal of Covid-19 vaccines should be to provide long-term protection against severe disease, hospitalization, and death. It is therefore important for studies of Covid-19 vaccines and boosters to evaluate not only short-term neutralizing antibody titers but also durability of antibody responses, memory B-cell responses, and cross-reactive T-cell responses.

soucre: NEJM