Taraz Samandari

T cell correlates of COVID-19 risk are poorly defined, particularly in people with HIV (PWH). CoVPN 3008 (NCT05168813) Part A was a prospective 14,002-participant cohort study that administered one or two doses of mRNA-1273 COVID-19 vaccine, depending on baseline SARS-CoV-2 serostatus, in participants (83% PWH) in sub-Saharan Africa. Participants self-monitored for prespecified COVID-19 symptoms, defined by Centers for Disease Control and Prevention symptom criteria. Previous work showed that protection from COVID-19 was superior for hybrid versus vaccine-induced immunity, and that neutralizing antibody titers inversely associated with COVID-19 risk. In the present work, we measured T cell responses to Spike and Nucleocapsid at baseline and 4 weeks post last-vaccination (Peak) in a case-cohort study and assessed them as correlates of risk. In Hybrid Group PWH (n = 22 cases), COVID-19 risk over 6 months decreased with increasing Peak Spike BA.4/5-specific CD4 + T cell responses, from 15.8%, 4.7%, and 0% risk at 0.1%, 0.2%, and 0.3% IFN-γ and/or IL-2 response magnitude, respectively. Including baseline Spike-specific neutralizing antibody titer and Peak CD4 + T cell functionality score in the same model increased the association’s strength (overall p < 0.001). Thus, CD4 + T cell responses are an independent correlate of COVID-19 risk among PWH with pre-existing SARS-CoV-2 immunity.

The relative efficacy, safety, and immunogenicity of monovalent mRNA-1273 (ancestral WA1) versus bivalent mRNA-1273.222 (ancestral plus omicron BA.4/BA.5) boosting have not been studied prospectively where HIV and SARS-CoV-2 seroprevalence are high. CoVPN 3008 (NCT05168813) was a randomized, double-blinded trial in seven African countries during omicron waves, enrolling people with HIV (PWH) or comorbidities associated with severe COVID-19 who had previously received mRNA-1273. Participants were randomized 1:1 to intramuscular monovalent or bivalent booster and routinely PCR-tested for SARS-CoV-2. Between 10/2022 and 03/2023, 3,988 participants (3,086 PWH) received bivalent (n = 2012) or monovalent (n = 1976) booster. By month 12, 293 COVID-19 cases and 221 asymptomatic infections occurred, including one severe case. COVID-19 rates did not differ between arms (hazard ratio [HR] 0.92, 95% CI 0.73–1.15, P = 0.45). Combined COVID-19 and asymptomatic infection was 15% lower with the bivalent (239 vs. 275; HR 0.85, 0.71–1.01, P = 0.07), and asymptomatic infection alone was 24% lower (HR 0.76, 0.59-1.00, P = 0.05). Neutralizing antibody titers to BA.4/5 and XBB.1.5, measured in 100 PWH per arm, boosted higher in bivalent recipients (P = 0.026 and 0.002). Adverse events were similar. In predominantly PWH, the bivalent booster was well tolerated, elicited superior immunogenicity against omicron variants, and appeared to protect against asymptomatic infection but not COVID-19.

People with HIV (PWH) are understudied in COVID-19 vaccine trials, leaving knowledge gaps on whether the identified immune correlates of protection also hold in PWH. CoVPN 3008 (NCT05168813) enrolled predominantly PWH and reported lower COVID-19 incidence for a Hybrid vs. Vaccine Group (baseline SARS-CoV-2-positive and one mRNA-1273 dose vs. negative and two doses). Using case-cohort sampling, antibody markers at enrolment (M0) and four weeks post-final vaccination (Peak) are assessed as immune correlates of COVID-19. For the Hybrid Group [n = 287 (195 PWH)], all M0 markers inversely correlate with COVID-19 through 230 days post-Peak, with 50% inhibitory dilution BA.4/5 neutralizing antibody titer (nAb-ID50 BA.4/5) the strongest and only independent correlate (HR per 10-fold increase=0.46, 95% CI 0.28, 0.75; P = 0.002). For the Vaccine Group [n = 115 (86 PWH)], Peak nAb-ID50 BA.4/5 correlates with reduced COVID-19 risk (1.9%, 1.1%, and 0.3% at titers 10, 100, and 1000 AU/ml) through 92, but not 165, days post-Peak. Using multivariable Cox analysis of binding and nAb, nAb titers predict COVID-19 in PWH. Two doses of a 100-µg Ancestral strain mRNA vaccine in baseline-SARS-CoV-2-negative individuals elicit sufficient cross-reacting Omicron antibodies to reduce COVID-19 incidence for 90 days post-Peak, but viral evolution and waning antibodies abrogate this protection thereafter.

MRNA vaccines have emerged as powerful tools for the prevention of infectious diseases, but subclinical malaria may reduce vaccine immunogenicity. We evaluated neutralizing antibody responses in asymptomatic HIV-infected adults with and without polymerase chain reaction-confirmed Plasmodium falciparum who received either monovalent mRNA-1273 or bivalent mRNA-1273.222 (WA-1 and BA.4/5) booster vaccines. In previous studies, a 50% pseudovirus inhibitory dose neutralizing antibody (ID50) titer of 1000 correlated with 96% efficacy in preventing COVID-19. We observed ID50 geometric mean titers >22 000 in both parasitemic and nonparasitemic participants 1 month after boosting. We conclude that COVID-19 mRNA vaccine antibody responses are unimpaired by concurrent asymptomatic parasitemia.

Whilst a quarter of the world’s population is estimated to be infected with Mycobacterium tuberculosis, it is unknown whether TB infection (TBI) increases the risk of severe COVID-19, which is relevant in TB-endemic settings, especially where HIV co-infection is also common. A convenience cohort of symptomatic and asymptomatic COVID-19 patients aged 8–80 years in western Kenya was followed daily for 14 days to assess disease progression using the validated inFLUenza-Patient-Reported-Outcome Plus signs and symptom tool. Nasal swabbing for SARS-CoV-2 was conducted to confirm the virus using polymerase chain reaction. QuantiFERON-TB Gold Plus was used to diagnose TBI. HIV status was based on self-reports. Between January 3, 2021, and January 20, 2022, 373 out of 387 participants had conclusive QuantiFERON results. At baseline, 5.9% (22/373) had self-reported severe COVID-19, 33.2% (124/373) had TBI, and 11.1% (38/341) reported being HIV-infected. Median follow-up of the cohort was 105 days (range 0–368). Self-reported severe COVID-19 was experienced by 10 of 124 (8.1%) participants compared with 12 of 249 (4.8%) without TBI (odds ratio [OR] 1.73, 95% CI 0.73-4.12, p = 0.21). HIV was not associated with self-reported severe COVID-19 (OR 3.13, 0.96-8.77, p = 0.039, adjusted OR 2.77, 95%CI 0.84-7.93, p = 0.070), but age ≥ 50 years was associated with self-reported severe COVID-19 (OR 3.73, 1.47-9.07, p = 0.004, adjusted OR 2.91, 95%CI 1.02-7.69, p = 0.035). One participant died of COVID-19 three days after diagnosis, and another participant developed active TB 128 days after his COVID-19 diagnosis and was successfully treated. Both were QuantiFERON positive. Self-reported severe COVID-19 was associated with older age and not TBI. Our finding that increased age was associated with self-reported severe COVID-19 is consistent with findings in multiple settings around the world.

Subclinical malaria may reduce the immunogenicity of mRNA vaccines. We evaluated neutralizing antibody responses in adults with (n=87) and without (n=221) PCR-confirmed Plasmodium falciparum who received a COVID-19 booster. Similar boosted ID50 geometric mean titers >22,000 in parasitemic and non-parasitemic participants suggests that COVID-19 mRNA vaccine responses are not impaired.

SARS-CoV-2 infections manifest with a broad spectrum of presentations, ranging from asymptomatic infections to severe pneumonia and fatal outcomes. This review centers on asymptomatic infections, a widely reported phenomenon that has substantially contributed to the rapid spread of the pandemic. In such asymptomatic infections, we focus on the role of innate, humoral, and cellular immunity. Notably, asymptomatic infections are characterized by an early and robust innate immune response, particularly a swift type 1 IFN reaction, alongside a rapid and broad induction of SARS-CoV-2-specific T cells. Often, antibody levels tend to be lower or undetectable after asymptomatic infections, suggesting that the rapid control of viral replication by innate and cellular responses might impede the full triggering of humoral immunity. Even if antibody levels are present in the early convalescent phase, they wane rapidly below serological detection limits, particularly following asymptomatic infection. Consequently, prevalence studies reliant solely on serological assays likely underestimate the extent of community exposure to the virus.

Background. SARS-CoV-2 infection in Africa has been characterized by a less severe disease profile than what has been observed elsewhere, but the profile of SARS-CoV-2–specific adaptive immunity in these mainly asymptomatic patients has not, to our knowledge, been analyzed. Methods. We collected blood samples from residents of rural Kenya (n = 80), who had not experienced any respiratory symptoms or had contact with individuals with COVID-19 and had not received COVID-19 vaccines. We analyzed spike-specific antibodies and T cells specific for SARS-CoV-2 structural (membrane, nucleocapsid, and spike) and accessory (ORF3a, ORF7, ORF8) proteins. Pre-pandemic blood samples collected in Nairobi (n = 13) and blood samples from mild-to-moderately symptomatic COVID-19 convalescent patients (n = 36) living in the urban environment of Singapore were also studied. Results. Among asymptomatic Africans, we detected anti-spike antibodies in 41.0% of the samples and T cell responses against 2 or more SARS-CoV-2 proteins in 82.5% of samples examined. Such a pattern was absent in the pre-pandemic samples. Furthermore, distinct from cellular immunity in European and Asian COVID-19 convalescents, we observed strong T cell immunogenicity against viral accessory proteins (ORF3a, ORF8) but not structural proteins, as well as a higher IL-10/IFN-γ cytokine ratio profile. Conclusions. The high incidence of T cell responses against different SARS-CoV-2 proteins in seronegative participants suggests that serosurveys underestimate SARS-CoV-2 prevalence in settings where asymptomatic infections prevail. The functional and antigen-specific profile of SARS-CoV-2–specific T cells in African individuals suggests that environmental factors can play a role in the development of protective antiviral immunity. Funding. US Centers for Disease Control and Prevention, Division of Global Health Protection; the Singapore Ministry of Health’s National Medical Research Council (COVID19RF3-0060, COVID19RF-001, COVID19RF-008, MOH-StaR17Nov-0001).

Antibodies are used to estimate prevalence of past infection. However, T cell responses against SARS-CoV-2 may more accurately define prevalence because SARS-CoV-2-specific antibodies wane. In November-December 2021, we studied serological and cellular immune responses in residents of rural Kenya who had not experienced any respiratory symptom nor had contact with COVID-19 cases. Among participants we detected anti-spike antibodies in 41.0% and T cell responses against ≥2 SARS-CoV-2 proteins in 82.5%, which implies that serosurveys underestimate SARS-CoV-2 prevalence in settings where asymptomatic infections prevail. Distinct from cellular immunity in European and Asian COVID-19 convalescents, strong T cell immunogenicity was observed against viral accessory proteins in these asymptomatic Africans, as well as a higher IL-10/IFN-γ ratio cytokine profile, suggesting that environmental or genetic factors modulate pro-inflammatory responses. Funding U.S. Centers for Disease Control and Prevention, Division of Global Health Protection. Singapore Ministry of Health’s National Medical Research Council under its COVID-19 Research Fund (COVID19RF3-0060, COVID19RF-001 and COVID19RF-008) and the Singapore Ministry of Health’s National Medical Research Council MOH-000019 (MOH-StaR17Nov-0001).

Background: Accurate and timely diagnosis is essential in limiting the spread of SARS-CoV-2 infection. The reference standard, rRT-PCR, requires specialized laboratories, costly reagents, and a long turnaround time. Antigen RDTs provide a feasible alternative to rRT-PCR since they are quick, relatively inexpensive, and do not require a laboratory. The WHO requires that Ag RDTs have a sensitivity ≥80% and specificity ≥97%. Methods: This evaluation was conducted at 11 health facilities in Kenya between March and July 2021. We enrolled persons of any age with respiratory symptoms and asymptomatic contacts of confirmed COVID-19 cases. We collected demographic and clinical information and two nasopharyngeal specimens from each participant for Ag RDT testing and rRT-PCR. We calculated the diagnostic performance of the Panbio^™ Ag RDT against the US Centers for Disease Control and Prevention’s (CDC) rRT-PCR test. Results: We evaluated the Ag RDT in 2,245 individuals where 551 (24.5%, 95% CI: 22.8–26.3%) tested positive by rRT-PCR. Overall sensitivity of the Ag RDT was 46.6% (95% CI: 42.4–50.9%), specificity 98.5% (95% CI: 97.8–99.0%), PPV 90.8% (95% CI: 86.8–93.9%) and NPV 85.0% (95% CI: 83.4–86.6%). Among symptomatic individuals, sensitivity was 60.6% (95% CI: 54.3–66.7%) and specificity was 98.1% (95% CI: 96.7–99.0%). Among asymptomatic individuals, sensitivity was 34.7% (95% CI 29.3–40.4%) and specificity was 98.7% (95% CI: 97.8–99.3%). In persons with onset of symptoms 7 days (157/876, 17.9%). The highest sensitivity was 87.0% (95% CI: 80.9–91.8%) in symptomatic individuals with cycle threshold (Ct) values ≤30. Conclusion: The overall sensitivity and NPV of the Panbio^™ Ag RDT were much lower than expected. The specificity of the Ag RDT was high and satisfactory; therefore, a positive result may not require confirmation by rRT-PCR. The kit may be useful as a rapid screening tool only for symptomatic patients in high-risk settings with limited access to rRT-PCR. A negative result should be interpreted based on clinical and epidemiological information and may require retesting by rRT-PCR.