key: cord-0683974-7w2cxnjy
authors: Liu, Jamin; Laurie, Matthew T; Rubio, Luis; Vazquez, Sara E; Sunshine, Sara; Mitchell, Anthea M; Hapte-Selassie, Matthias; Mann, Sabrina A; Pilarowski, Genay; Black, Douglas; Marquez, Carina; Rojas, Susana; Lionakis, Michail S; Petersen, Maya; Whitman, Jeffrey D; Jain, Vivek; Anderson, Mark; Havlir, Diane; DeRisi, Joseph
title: SARS-CoV-2 transmission dynamics and immune responses in a household of vaccinated persons
date: 2022-01-17
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac029
sha: 5c374ca5dafde732aa6c348a4022263fc2437395
doc_id: 683974
cord_uid: 7w2cxnjy

While SARS-CoV-2 vaccines prevent severe disease effectively, post-vaccination ‘breakthrough’ COVID-19 infections and transmission among vaccinated individuals remain ongoing concerns. We present an in-depth characterization of transmission and immunity among vaccinated individuals in a household, revealing complex dynamics and unappreciated comorbidities, including autoimmunity to type1 interferon in the presumptive index case.

COVID-19 has caused over 230 million cases of infection worldwide, leading to more than 4.7 million deaths due to coronavirus disease (COVID-19) [1] . Global vaccination efforts have so far administered 6.1 billion vaccine doses [2] . In the United States, three FDA-authorized vaccines have been widely distributed: BNT162b2 by Pfizer/BioNTech, mRNA-1273 by Moderna, and JNJ-78436735 by J&J/Janssen. Each has demonstrated, through clinical trials and retrospective studies, the capacity to prevent symptomatic infection and severe disease [3] .

Approximately 50% of the United States population is considered fully vaccinated. Many households have mixed populations of adults and children with variable completion of COVID-19 vaccination [2] . Furthermore, most SARS-CoV-2 lineages have been outcompeted and replaced by newer variants of concern including the Delta and Gamma variants. Further, many spike protein mutations associated with neutralizing antibody escape (K417N/T, R346K, L452R, T478K, E484K/Q, N501Y) have emerged [4, 5] . Given these factors, COVID-19 infections in fully vaccinated people (i.e., breakthrough) are well documented [6] . However, there have been relatively few detailed studies to date of household transmission trajectories, especially in households with individuals who received different vaccines, or who have different vaccine completion statuses.

Here, we describe a household cluster of Gamma variant COVID-19 cases occurring in vaccinated family members living in co-residence that resulted in mixed clinical outcomes. A detailed inspection of the epidemiological and clinical features of these cases, together with serology testing and genomic sequencing, suggest complex factors including partial immunity and unrecognized underlying autoimmunity, as potential contributors to breakthrough infections. Our data add to A c c e p t e d M a n u s c r i p t rapidly emerging literature on SARS-CoV-2 transmission dynamics within households of vaccinated persons.

Individuals 1-5 lived together in the same residence, where they ate, slept, and socialized with one another in an unmasked setting. Individual 6 lived separately but frequented the home of Individuals 1-5. Together, these individuals also attended weekly community events, such as religious services, together as one large group. Each individual was thus exposed to one another either through co-residence or frequent visitation. Table 2 ). Characteristic mutations of concern (K417T, E484K, and N501Y) were observed [4, 5] . Analysis of the consensus genomes from Individuals 2 and 3 revealed only a single nucleotide difference (G17122T, leading to a ORF1b:A1219S amino acid substitution).

Serum samples from the five household members were analyzed for SARS-CoV-2 neutralizing antibodies using a pseudovirus neutralization assay [7] . Sera from members of this household demonstrated a wide range of neutralization ( Figure 1B) The neutralization efficacy of patients' sera against the Gamma variant pseudotype was approximately 2-fold lower than the measured NT 50 against wild-type virus (D614G spike mutation only). This observation is consistent with previously described decreases in neutralization against variants, especially those harboring mutations at E484K [4, 5, 8 ].

Additionally, we tested for anti-IFN-α2 auto-antibodies, a marker correlated with severe COVID-19 and poor patient outcomes [9, 10] . Using serum from patients with Autoimmune Polyglandular Syndrome Type 1 (APS1), an autoimmune syndrome where patients frequently develop an abundance of anti-IFN-α2 antibodies, as a benchmark for verified interferon autoimmunity, we measured for anti-IFN-α2 antibody presence using a radioligand binding assay (RLBA) [9] . Serum from Individual 1, who had the most severe response to infection, exhibited positive anti-IFN-α2 antibody signal while the other family members had negative titers ( Figure 1C) . [10] . Although the presence of such auto-antibodies can be clinically silent, they appear to play an influential role in patient outcomes for SARS-CoV-2 infection [12] .

Comorbidities such as autoimmune caused by anti-IFN auto-antibodies can lead to decreased protection against circulating variants with spike mutations conferring neutralization escape and thus raise the risk of breakthrough infections [10] . With household exposure to COVID-19, even fully vaccinated individuals with typical levels of neutralizing antibodies are at risk of infection. This data is strongly consistent with intrahousehold transmission amongst three vaccinated household members in this study, and this data highlights the inherent complexities of individuals, including unrealized underlying autoimmunity, that may contribute to transmission dynamics. This data supports the urgency for continued vaccination, boosters, and next-generation vaccines that contain mutations known to confer immune escape potential.

A c c e p t e d M a n u s c r i p t M a n u s c r i p t Table 3 ). For the healthy vaccinated donor cohort, geometric mean titer (dashed lines), interquartile range (boxes), and full range (shaded region) and shown for D614G (black) and Gamma (red) pseudoviruses. NT 50 values for Gamma variant pseudovirus were approximately 2-fold lower than D614G pseudovirus for the healthy vaccinated cohort and most household members sera, apart from Individual 2. All household member serum neutralization titers were within or above the range of healthy donor titers except for Individual 1, whose neutralization titers for D614G and Gamma were 4.4-fold and 6.3-fold lower than healthy controls, respectively. (C) Detected by radioligand binding assay reveals that Anti-IFN-α2 auto-antibodies are absent from all assayed pre-pandemic healthy controls (n=42) and vaccinated healthy controls (n=11) [8] . In this household, only Individual 1 demonstrated presence of anti-IFN-α2 auto-antibodies. Autoimmune Polyglandular Syndrome Type 1 (APS1) patient sera are used as positive controls [11] ; negative controls are from pre-COVID healthy blood donor plasma or the healthy vaccinated donor cohort.

A c c e p t e d M a n u s c r i p t 

Our World in Data: Coronavirus Pandemic (COVID-19)

Effectiveness of COVID-19 Vaccines in Preventing Hospitalization Among Adults Aged ≥65 Years -COVID-NET, 13 States

Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Breakthrough Infections of SARS-CoV-2 Gamma Variant in Fully Vaccinated Gold Miners

A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Exposures to different SARS-CoV-2 spike variants elicit neutralizing antibody responses with differential specificity towards established and emerging strains

Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19

Autoantibodies against type I IFNs in patients with lifethreatening COVID-19

Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

We would like to thank Dr. Chuka Didigu, Dorothy Park CRNA, Salu Ribeiro, and Bay Area Phlebotomy and Laboratory services for performing blood draws of study subjects. We thank Dr.Andreas Puschnik for providing the engineered cell line used in this study. We thank Drs. Peter Kim, Don Ganem, Sandy Schmidt, and Cori Bargmann for technical assistance and discussion. 

Dr. DeRisi is a member of the scientific advisory board of The Public Health Company, Inc., and is a scientific advisor for Allen & Co. Dr. DeRisi also reports stock options granted for service on A c c e p t e d M a n u s c r i p t