Live Unattenuated/Attenuated Virus Vaccines for COVID-19

2021-10-04, preprint, self-published Cochrane-style

Live Unattenuated/Attenuated Virus Vaccines for COVID-19

Leo Goldstein


Among the many vaccine technologies attempted for COVID-19 vaccines, the oldest technology – live unattenuated virus (LUV) vaccine – has hardly been mentioned. For the purposes of this article, a LUV vaccine refers to the process of administering a small amount of unattenuated virus in conjunction with the anti-viral against it [1].

The first vaccine against yellow fever used the live virus mixed with  [2], using antibodies-rich serum from recovered individuals [2]. Another underused vaccine type against COVID-19 is a live attenuated virus (LAV) vaccine [3] [4]. LAV is the mainstay of modern vaccination [5] [6] [7]. Both LUV and LAV provide the broadest immunity because they elicit immune response to antigens presented by the virus in all replication phases. LAV for respiratory diseases is usually administered intranasally, providing not only systemic, but also mucosal immunity. Mucosal immunity is sterilizing, preventing infection and transmission of the coronavirus.


The 2020 strains of SARS-COV-2 was very sensitive to a live unattenuated virus vaccine due to the typical mildness of the disease and the existence of effective antivirals (like HCQ and IVM) and oropharynx antiseptics (such as PVP-I). The current Delta variant is not as mild as those that circulated in 2020.

Luckily, the recent successes in genome sequencing allow for the selection of the virus’ strains and genomes, which are less dangerous than the dominant strain, but represent them well before the immune system. This may be called “naturally attenuated” virus. Intranasal administration of such a “naturally attenuated” coronavirus, preceded and/or followed by antiviral treatment against it, might be a very effective vaccination against COVID-19. The antivirals include Ivermectin and/or Hydroxychloroquine + Zinc [8]. Additionally, repetitive mouth washing, gargling, and nasal drops or spray with PVP-I, for a few days, should be effective in slowing down the infection and in preventing transmission to others [9]. The ideal vaccine would combine the best properties of LUV and LAV. An emergency vaccine would be on a spectrum between a live unattenuated and attenuated virus (LUAV).

Only a tiny amount of the coronavirus is needed, probably much less than 105 virions (corresponding to 100-1,000 infectious units). This is significantly less than the 51010 of viral particles (2.5108 infectious units) per dose of adenovirus-vectored spike vaccines [10], [11], or the ~1011 in a COVID-19 patient.

Compared to a natural infection, such a LUAV vaccine would select a less dangerous SARS-COV-2 strain, minimize the initial amount of the inoculum, and start anti-viral treatment early, before any symptoms appear.

The amount of the virus, virus strain, and antiviral regime (when to start and in what order) can be individually tailored, based on the age, comorbidities, and immunity status.

The shortcoming is that shedding infective virus and infecting others immediately after LUAV vaccination is possible. This said, an individual getting mRNA vaccine amid the coronavirus epidemic is also likely to become infected and to shed the virus because of temporary weakening of the immune system [12].

Conventional LAV takes a long time to develop and test. Old methods of attenuating (like growth at lower temperature) risk losing key antibodies-targeted epitopes. Novel methods, such as codon pairs deoptimization, used in COVI-VAC, have unknown consequences and long-term effects.

Selection of Strain

We are currently dealing with the Delta strain, which has a faster growth rate and is highly resistant to current vaccine elicited immunity. Most of this resistance is conferred by two mutations in the spike receptor binding domain (RBD) – S:L452R and S:T478K. Less important is the mutation S:T19R in the N-terminal domain

The optimal genome for a LUAV vaccine would be one with the mutations S:L452R and S:T478K, but without other dangerous mutations.

For example, there is a whole variant B.1.629 with the S:L452R and S:T478K mutations [13]. However, it also contains some other dangerous mutations. Genomes with L452R and T478K combination were sequenced starting with September 2020 [13]. GISAID contains many promising sequences.

Replicating a genome, which has already arisen multiple times but failed in evolutionary competition, is safer than creating a new one.

No Competing Interests

The author declares no competing interest. No funding was provided for this work.


This is not medical advice.

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1 thought on “Live Unattenuated/Attenuated Virus Vaccines for COVID-19

  1. Do you see any evidence for live/unattenuated/attenuated vaccines being more successful than mRNA vaccines? Are you yourself going to take one of the whole virus vaccines being used today?
    Why do you think that ‘This is significantly less than the 51010 of viral particles (2.5108 infectious units) per dose of adenovirus-vectored spike vaccines, or the ~1011 in a COVID-19 patient’? What is the rational? Do you have any data to back this up?

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