Live oral SARS-CoV-2 vaccine provides partial protection in Rhesus Macaques

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide, despite the high coverage of coronavirus disease 2019 (COVID-19) vaccines. Alternative vaccine technologies have therefore been explored, including live inactivated virus vaccines.

Study: Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery Against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques. Image Credit: Robert Ross/ Shutterstock

A new study, available on the bioRxiv* preprint server, describes the partial protection against respiratory infection with SARS-CoV-2 following gut inoculation with a live attenuated virus.


The messenger ribonucleic acid (mRNA) vaccines from Moderna and Pfizer were the first to receive emergency approval against COVID-19, and millions of doses have been rolled out so far.  

More vaccines are urgently required with better logistical features as large gaps in vaccine availability remain, especially in developing countries. The emergence of vaccine-resistant variants only increases this need further.

The abundance of lymphoid tissue in the gut offers an opportunity to elicit a robust immune response that may spill over to protect against the entry of the virus into the respiratory tract. The response may be qualitatively different from that of the mRNA vaccines, while the live virus may be weakened further by its exposure to the gut milieu.

Live oral vaccines are simple to develop, can be produced rapidly, inexpensive, and easily distributed and administered. Moreover, lower doses are usually adequate to elicit protective immunity. These features point to their advantages in low-resource settings.

Some live oral vaccines currently licensed for human use include those against adenovirus serotypes (Ad4 and Ad7) that cause respiratory infection, the oral polio vaccine, and the rotavirus vaccine.  

What did the study show?

The current study was a proof-of-concept work to evaluate the immunogenicity and protective efficacy of live SARS-CoV-2 when delivered to the gut in macaques. They found that after inoculation into the macaque duodenum, they observed viral shedding in the stools on the first post-inoculation day, but not after that, except in one of the 21 animals. This one continued to shed for over three weeks.

Genomic RNA, indicating viral replication, was also observed in almost half the tested cases (4/9), and the virus was detected in rectal swabs in two animals at 21 days. Subgenomic RNA (sgRNA) transcripts were found to a limited extent in vaccinated animals. No viral shedding occurred from the respiratory tract, nor was the virus detectable in serum or saliva.

The results suggest that the virus was rapidly excreted from the gut, with little replication. However, at four weeks from inoculation, low titers of neutralizing antibodies were observed in the serum in 7/9 macaques, compared to undetectable titers in the controls. No mucosal antibodies were detected.

Protection against viral challenge

At week four, the vaccinated animals were challenged with the virus intranasally and intratracheally. They were found to have low viral loads, with 1.61 and 1.59 log reductions in the peak sgRNA in the lung and nasal swabs, respectively, indicating partial protection against respiratory challenge with SARS-CoV-2 following vaccination.

Two weeks later, mild interstitial pneumonia was found in all challenged animals, irrespective of vaccination status. At week four, the neutralizing antibody titer showed a negative association with the peak sgRNA copy number in both lung fluid and nasal swab specimens. There was no link between stool viral shedding and the sgRNA copies/mL, however.

What are the implications?

The study demonstrates that live virus delivery to the gut induced modest partial protection against future viral challenges. The degree of protection correlated with serum neutralizing capacity.

While offering hope that a live oral vaccine may eventually be feasible, the limited immune response and a slight degree of protection underline the extent of work required to achieve this. An explanation for the poor immunogenicity of the live oral virus inoculate may lie in the rapid viral shedding observed in the stool, with little evidence that the virus replicated in the gut.

An earlier study showed productive and durable gut infection with the virus when introduced into the stomach, indicating that differences in the inoculum, technique, site of vaccination, and the type of animal may all affect the final result.

Improving the antigenic load and presentation in the gut may be possible using encapsulation and better formulation, which allows the virus to survive in the lumen long enough to replicate. Repeated or higher doses may also be required. With such changes to the delivery systems, vaccination schedule, and vaccine dosage, live oral SARS-CoV-2 vaccines may become a reality.

*Important notice

bioRxiv 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.

Journal reference:

  • Yu, J. et al. (2021) “Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery Against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques”. bioRxiv. doi: 10.1101/2021.09.13.460191.
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