What makes the measles vaccine so effective compared to other vaccines?

Question

The measles vaccine (administered alone or as part of a combination vaccine like MMR) seems to be incredibly effective on a range of criteria, namely:

• Frequency: 1-2 doses required during lifetime.
• Age: Safe to give to young children (e.g. the NHS gives the first dose at 12 months), so there's a limited window for infection before vaccination - and particularly before children start to mix at school.
• Effect: Reduces the likelihood of infection to close to immunity.
• Duration: Effects appear to be very long-lasting, possibly life-long.

Many other vaccines seem to perform worse on at least one of the above, e.g. they require annual doses, reduce the severity of symptoms rather than the likelihood of infection, or can't be given to very young children.

What is it about this particular vaccine (and the virus it targets) that makes it so effective, even though it was developed before some breakthrough technologies such as mRNA?

Answer 1

First, it's not just the vaccine: immune responses just to measles itself are themselves strong and long-lasting, and reinfection is rare (see https://en.wikipedia.org/wiki/Measles). My understanding is that it is not entirely known why exposure to some pathogens results in longer lasting immunity than others, but there are some known contributing factors.

One factor is that from the perspective of the immune system, some pathogens are not really one pathogen but a group of them that all look different to the immune system because they have distinct surfaces; we call these major groups serotypes. For a virus like influenza, there are many serotypes. For measles virus, there is just one: if your immune system is able to recognize one measles virus it can recognize them all. Even though there is genetic variation in measles, the surface parts recognized by the immune system are quite constant.

Further, antibodies recognize several distinct sites on the measles surface glycoproteins. Changes in just one of these sites don't really help the virus escape immune detection, so there isn't much natural selection for those mutations.

Another, related, factor is the host. Humans are the only host for measles virus. Relatively widespread vaccination of humans means that there is a limited population for the virus to reproduce and create new variations in. Other viruses that affect humans can spread and mutate in other animal hosts and then spread back to humans. That can be a mechanism to eventually accumulate mutations that make the virus's surface very different from the original strain and therefore difficult for the immune system to detect.

In summary, the things that make the measles vaccine effective are really just traits of the measles virus. We struggle to make effective vaccines against viruses that change a lot, that don't themselves evoke long-lasting immunity, or that use specific mechanisms to disable or evade the immune system.

Answer 2

Live attenuated vs inactivated or "subunit" vaccines There is a key difference between measles and influenza vaccines. Measles is a live attenuated vaccine (it's a live virus), just like yellow fever virus and these vaccines provide the very best protection, which is widely considered to be life-long. This has been challenged with yellow fever virus, but it is nevertheless highly efficacious

Influenza vaccine is an inactivated vaccine so the presentation to the immune system is impaired.

Most vaccines are not attenuated because it's risky, i.e. if they revert they'll cause an active infection and thereon can be transmitted. Polio is an exception, which is attenuated, and offers superb immunity.

Moreover, when a virus and attenuated vaccine virus enters a cell it undergoes a conformational change when its infecting the host cell (all viruses do this) and antibodies that bind to the virus at this stage of the life cycle will point blank block infection, i.e. they stop the virus entering the cell. If a virus can't enter the cell - it's dead, the technical word for this is "neutralised". An antibody just binding to the virus doesn't necessarily stop the virus infecting the cell and in limited cases it can enhance its ability to infect (antibody dependent enhancement). An inactivated vaccine has a lot of difficulty correctly undergoing a conformational change to "lock onto" the host cell - it's already dead prior entering the body.

A live vaccine generates a massively better immunity, exposing more of the proteins used in its life-cycle to antibodies and a lot more neutralising antibodies. Antibody memory can be life-long.

I'm not mentioning cellular immunity because that has a shelf-life (arguably six months, probably longer).

---

Genetic diversity The issues about low genetic diversity of measles are also valid. Measles is a bit like holding the same two cards in a poker hand - every hand, sooner or later it can't win because everyone knows what the cards are.

Influenza's genetic diversity is really large, it's a bit like choosing from two suites of cards in a poker hand and the solution can be any combination. Thats hard to memorise (for the immune system). Specifically, influenza in particular flips/changes is antigenic coat making it difficult for antibody memory between infections to be effective. Influenza's potent trick of 'flipping', measles can not do. Influenza has a segmented genome and can switch its protein coat by "mixing" its two different key surface proteins involved in the infection life-cycle ('mixing theory'). Its technically called "antigenic shift" and measles can't do it because it has a single stranded RNA genome.

---

See the bibliography for further details especially Oxford's "Human Virology".

---

Bibliography

"Human Virology" by John Oxford, Kellam and Collier by Oxford Press Fifth Edition 2016 See chapters on Polio, Measles and Influenza

This is text is the most comprehensive virology text at graduate level virology and covers all the material described above. The only downside is there is no sixth edition. Yellow fever virus is poorly covered here and the vaccine is omitted. Yellow fever virus is in the chapter Flavivirues.

Fields Virology: Emerging Viruses 7th Edition 2021 by Peter M. Howley MD, David M. Knipe PhD, Sean Whelan

This is more specialist, but covers SARS-CoV-2 and yellow fever virus, which are not really covered in the "Human Virology" by John Oxford.

For in depth genomics: Principles of Molecular Virology by Alan Cann is a standard text, but "Human Virology" is sufficient ESPECIALLY for influenza. John Oxford was an influenza investigator

---

Comment polio vaccine

@JenserCube raised the issue of Polio live attenuated vaccine. This is really a separate question but what they are requesting, I'd prefer to avoid talking about because criticism of the polio vaccine got mixed up with conspiracy theory and of course the current health czar for the USA is a vaccine skeptic. There is a recent trend toward replacing the polio vaccine with a "subunit" vaccine (the old term), basically a reverse genetics based vaccine. A number of publications are proposing this. I'm personally not aware of a current phase 2 trial (the minimum requirement to say there's a series alternative). Thus I would simply say the polio vaccine has been incredibly successful and arguably came close to global eradication (in which case we'd no longer need a vaccine). So my personal view, whilst aware of the counterpoints, is stay the course, hold our nerve and get shut of this infectious disease once and for all.

I am well aware that this is an active research base towards an alternative vaccine, but my personal view is hold the course of global eradication, because once thats done - polio virus is gone the same way smallpox was erradicated.

I honestly can't compromise a long-term, heartfelt viewpoint for a few upvotes or down-votes particularly moving into an era that could turn decisively 'anti-vaccine'. One current vaccine at phase 3 I helped build the molecular foundations of it, so I've a track-record in reverse genetic vaccine design.