New York City SARS-CoV-2 breakthrough cases predominantly Alpha and Iota variants

While Delta (B.1.617.2) has overtaken Alpha (B.1.1.7) as the dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant in the United States, Alpha remained a force to be reckoned with in New York City earlier this year. New research published on the preprint medRxiv* server details breakthrough infections in vaccinated and unvaccinated individuals living in New York City.

The majority of infections came from either Alpha or the Iota (B.1.526) variant. The research team found no evidence of variants being more prevalent in the vaccinated population than in the unvaccinated.

Study: Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City. Image Credit: NIAID

How they did it

The researchers performed SARS-CoV-2 genome sequencing in individuals who were positive for COVID-19 after 14 days or more from when they completed their vaccinations with any of the three approved FDA vaccines. The control group consisted of participants randomly selected for genomic surveillance that tested positive for COVID-19 but who were unvaccinated. All participants were a part of the NYU Langone Health system with hospitals in the New York City metro area and Long Island.

They evaluated variant distribution and mutation rates at every residue in spike between vaccinated and unvaccinated individuals.

Breakthrough infections in vaccinated individuals

A total of 126,367 individuals were fully vaccinated by April 30, 2021, with 98% getting vaccinated with an mRNA vaccine. Of these vaccinated individuals, there were 86 coronavirus cases — 69 had Pfizer/BioNTech, 16 had Moderna, and 1 had the Johnson & Johnson vaccine — between February 1 and April 30.

About 80% of cases yielded full SARS-CoV-2 genomes that gave enough information for researchers to trace back the virus’s lineage.

A total of 7 individuals with full SARS-CoV-2 genomes required hospitalization, and one person died.

Maximum likelihood tree of SARS-CoV-2 vaccine breakthrough, unvaccinated matched control, and global reference sequences. IQ tree of 5,056 SARS-CoV-2 full genome sequences (base pairs 202-29,657 according to Wuhan-Hu-1 as reference), including 67 vaccine breakthrough (orange) and 1,187 unvaccinated control SARS-CoV-2 sequences from our NYU cohort (greater NYC area) (purple) together with 1,361 other US (cyan) and 2,441 non-US global reference sequences (black). The tree was generated with a GTR+I+G substitution model and 1,000 bootstrap replicates, and the substitution scale of the tree is indicated at the bottom right. The branches of the tree are colored as indicated. Vaccine breakthrough sequences are additionally highlighted by orange triangles as branch symbols and gray rays radiating from the root to the outer rim of the tree. Hospitalizations due to COVID-19 among the vaccine breakthrough infections are indicated by black triangles (h). The variants responsible for most vaccine breakthrough infections in our study cohort are labeled with respective Pango lineages (WHO classification in parenthesis).

Prevalence of Alpha and Iota variants in New York City

Among the 67 infections with full SARS-CoV-2 genomes, about 38.8% were from Alpha, and 41.8% were from the Iota variant and its sublineages B.1.526.1 and B.1.526.2. Only 1 case was from Gamma (P.1), and 17.9% came from other variants.

Coronavirus infections from the Alpha variant were linked to a higher viral load in the body. Although, the amount of viral load did not differ significantly with infections caused by the Iota variant.

In unvaccinated individuals, the researchers sequenced 1,187 SARS-CoV-2 sequences. Alpha caused about 29.1% of infections, and 41% came from Iota and its sublineages.

Twelve cases or 1% of infections were from Gamma, and 28.9% were from other miscellaneous variants.

There were 7 hospitalizations in unvaccinated individuals: 5 patients had COVID-19 from Alpha, and 2 patients had cases from the Iota variant.

Further analysis showed no difference in contracting a variant of interest or a variant of concern in COVID-19 positive vaccinated and unvaccinated individuals. The results correspond with genomic sequencing during February and April 2021 that confirmed that Alpha and Iota were circulating in New York City at the time.

“Accordingly, our vaccine breakthrough samples mostly engaged B.1.1.7 and B.1.526 clades and were interspersed among the unvaccinated controls as well as other United States sequences. There was no evidence of extensive clustering that might indicate onward transmissions or transmission chains of vaccine breakthrough infections. Instead, they were widely distributed and appeared to mostly involve independent clusters of infections,” wrote the researchers.

Spike protein mutations helped with breakthrough infections

In the 67 vaccine breakthrough infections and the 1,187 unvaccinated infections, the spike mutations were at 233 more amino acid residues compared to the original strain.

Most mutations occurred in unvaccinated individuals, and only the D614 site was equally mutated in both groups. However, 41 sites showed more mutations rates in vaccinated individuals infected with COVID-19.

“Interestingly, the degree of enrichment was higher at the 41 breakthrough-enriched sites compared to the 191 sites enriched in controls. Contributing factors presumably included random mutations in the absence of immune pressure in controls, adaptive selection of immune escape mutations in vaccine breakthroughs, but also uneven case numbers in both groups,” wrote the team.

When disregarding unique mutations in the dataset, the 41 mutation sites decreased to 21 in the vaccinated group.

The mutations appeared to be more N-terminal domain deletions, receptor-binding domain mutations, —K417, S477, E484, and N501— mutation near the furin binding site, and C-terminal domains. All of these mutations are associated with immune evasion or increased ACE2 receptor binding.

The researchers wrote, “In conclusion, our data indicate that vaccine breakthrough in fully mRNA-vaccinated individuals is not more frequent with the VOC Alpha or the NY local VOI Iota, which underlines the high efficacy of mRNA COVID-19 vaccines against different variants. The Alpha variant appears overrepresented in the hospitalized group, though the low case numbers of hospitalizations do not allow firm conclusions. The increased presence of mutations in key regions of the spike protein in the vaccine breakthrough group is of potential concern and requires continued monitoring. Genomic surveillance of vaccine breakthrough cases should be carried out on a broader scale throughout the United States and the entire world to achieve higher case numbers and the inclusion of different VOCs and VOIs.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.